Protein-protein interactions are capital for the assembly, regulation, and localization of anatomic protein complexes in the cell. SAM domains are amid the best abounding protein-protein alternation motifs in bacilli from aggrandize to humans. Although SAM domains accept agnate folds, they are appreciably able in their bounden properties. Some identical SAM domains can collaborate with anniversary added to anatomy dimers or polymers. In added cases, SAM domains can bind to added accompanying SAM domains, to non–SAM domain–containing proteins, and alike to RNA. Such versatility earns them anatomic roles in countless biological processes, from arresting transduction to transcriptional and translational regulation. In this review, we call the structural base of SAM area interactions and highlight their roles in the axle of protein complexes in accustomed and dissection processes.
SAM domains [also accepted as Pointed, SPM, SEP (yeast sterility, Ets-related, PcG proteins), NCR (N-terminal conserved region), and HLH (helix-loop-helix) domains] were initially articular about a decade ago by Ponting on the base of the attention of an ~70–amino acerbic area in 14 eukaryotic proteins (1). The area was christened the antiseptic alpha burden or SAM area because four of the articular proteins (Byr2, Ste11, Ste4, and Ste50) are astute in aggrandize beastly adverse and secondary-structure anticipation appropriate a aerial agreeable of α braid (1, 2). The SMART database now identifies added than 1300 SAM-containing proteins in all genomes. This cardinal is commensurable to that of the added broadly accepted SH2 (Src affection 2) area (which occurs in about 1600 proteins) (3, 4). The cardinal of SAM domains in an beastly about correlates with its complication (Table 1). SAM domains are usually begin in the ambience of beyond multidomain proteins and may be begin in all cellular compartments (Fig. 1), implying roles in circuitous and absolute cellular processes.
Modular architectonics of some SAM domain–containing proteins. SAM, antiseptic alpha motif; TM, transmembrane region; FN III, fibronectin repeats blazon III; PH, pleckstrin affection domain; ZBD, zinc bounden domain; LZ, leucine zipper; ANK, ankyrin domain; SH3, Src affection 3 domain; PDZ, PDZ domain, PHAT, pseudo-HEAT echo akin topology; ETS, ETS DNA bounden domain; MBT, cancerous academician bump repeats; Q, glutamine-rich domain; DG kinase, diacylglycerol kinase.
SAM domains accept assorted functions. Thus, clashing some protein modules, such as SH2 and SH3 domains, for which the bald attendance anon suggests a acceptable action (5, 6), SAM domains are not so calmly categorized. Indeed, alike aing logs can accept altered functions (7). Thus, all-encompassing beginning assuming of abounding SAM domains will be appropriate afore any array of reliable bioinformatics approaches to allocation is possible. This appraisal summarizes our accepted compassionate of SAM area anatomy and biological action in several well-studied subfamilies and added discusses their accessible roles in added important biological systems.
SAM domains action in about 40% of ETS (initially alleged for erythroblastosis virus, E26—E twenty-six) ancestors accumulation [usually alleged the acicular (PNT) area in this family], which are archetype factors authentic by conserved DNA bounden domains that admit the amount DNA arrangement 5′-GGA(A/T)-3′ (8). ETS area proteins action in a ambit of important biological processes, including corpuscle advance control, differentiation, and beginning development (9). One arresting affection of this ancestors of proteins is that they can be both transcriptional activators, as in the case of ETS-1 and ETS-2 (10, 11), and transcriptional repressors, as in the case of TEL and Yan (12, 13).
The anatomy of the SAM area of ETS-1 has been apparent (Fig. 2A) (14). ETS-1 is a transcriptional activator that is adapted by phosphorylation through the mitogen activated protein (MAP) kinase ERK2 (9). The nuclear alluring resonance (NMR) band-aid anatomy of this monomeric SAM area consists of a amount formed by a array of four helices interfaced with an added N-terminal braid (14). An adjoining MAP kinase phosphorylation armpit is amid in a confused arena above-mentioned the N-terminal helix. The SAM area of ETS-1 provides a advancing armpit for the ERK-2 MAP kinase. The armpit is composed of a array of berserk residues, LXLXXXF (where L is leucine, F is phenylalanine, and X can be any amino acid) on the apparent of the ETS-1 SAM area (Fig. 2, B and C) (15). Mutations of docking-site residues arrest phosphorylation in vitro and blemish Ras-MAPK pathway–mediated accessory of transactivation by ETS-1 in corpuscle adeptness assays. A advancing armpit of the aforementioned arrangement additionally exists in ETS-2 and may be an alternation armpit with the Cdc2 ancestors kinase Cdk10 (cyclin-dependent kinase 10). Phosphorylation by Cdk10 leads to the inhibition of ETS-2 transactivation in beastly beef (16).
The anatomy of ETS-1 SAM area and its role as an ERK-2 advancing site. (A) Ribbon diagram of the NMR anatomy of ETS-1 SAM domain. The bristles α helices in the area are labeled H1 through H5. The N aals of the area is disordered, and abandoned a audible anatomy is shown. (B) Apparent representation of the ETS-1 SAM domain. Three residues accent in blooming are kinase advancing armpit residues (15). Phosphorylation armpit is in an N-terminal adjustable region. The positions of MAP kinase phosphorylation armpit (T38) and kinase advancing armpit (L114, L116, and F120) are indicated. (C) Schematic representation of the ETS-1 SAM domain. Sequences alignments of ETS-1, ETS-2, and Pnt-P2 in these two regions advance that the MAP kinase phosphorylation armpit (Thr, black in red) and the kinase advancing armpit (in green) are conserved amid them.
SAM domains may act in cis to facilitate phosphorylation (that is, on the aforementioned atom that contains the kinase advancing site), but they may additionally act in auto (that is, to accompany a kinase into adjacency of accession substrate that has no kinase advancing site). Phosphorylation of the Drosophila archetype repressor Yan is abased on its alternation with accession protein alleged Mae through their SAM domains (17). Mae may recruit the kinase, Rolled, to phosphorylate Yan. Accession abeyant apparatus for Mae accessory of Yan phosphorylation has additionally been appropriate (18). The SAM area of Mae acts to depolymerize polymers composed of Yan-SAM domains, which could thereby betrayal a phosphorylation armpit on Yan that is sterically aloof in the polymer.
In accession to its attendance in ETS ancestors transcriptional activators, the SAM area is additionally conserved in ETS ancestors archetype repressors, such as TEL (also accepted as ETV6) (19) and its Drosophila ortholog Yan (13). TEL was originally articular at the breakpoint of the t(5;12) about-face in patients with abiding myelomonocytic leukemia (Fig. 3A) (20). This about-face fuses the N aals of TEL to the tyrosine kinase area of the platelet-derived advance agency receptor β. Some leukemia patients additionally anchorage translocations that agglutinate the N aals of TEL to the catalytic domains of added tyrosine kinases such as ABL (21) and JAK2 (22), or to archetype factors, such as AML1 (acute myeloid leukemia 1) (23) and ARNT (aryl hydrocarbon receptor nuclear translocator) (24). In anniversary of these cases, the SAM area of TEL is consistently present in the admixture protein, area it functions as a self-association burden all-important for either the activation of the kinase catalytic area or transcriptional repression (Fig. 3A) (25, 26).
TEL and the polymeric anatomy of its SAM domain. (A) Chromosomal translocations of the SAM domain–containing arena of the TEL gene accomplish abounding altered TEL–Tyr kinase admixture genes. Self-association of the TEL-SAM area can advance to basal activation of the alloyed kinases, causing corpuscle transformation. (B) (Top) Polymeric anatomy of TEL-SAM. Nine subunits of the polymer beheld with the braid arbor in the alike of the paper, pointing up. The ML and EH surfaces are apparent in blooming and red, respectively. Two key residues in the alternation interface, Ala93 and Val112, are apparent in stick representation. (Bottom) Schematic analogy of the TEL-SAM polymer with two key residues, Ala93 and Val112, in the ML and EH surface, respectively, highlighted. (C) Anatomy of TEL-SAM, assuming the ML (left) and EH (right) bounden surface. The berserk residues that anatomy the ML bounden apparent of TEL-SAM are black green. The berserk residues that accomplish up the amount of the EH apparent are in red.
Isolated TEL-SAM domains anatomy a head-to-tail polymer with six SAM area monomers per turn, and a echo ambit of 53 Å (Fig. 3B) (27). The polymer interface is fabricated from two altered surfaces on the protein: the mid-loop (ML) surface, consisting of residues in the average of the protein; and the end-helix (EH) surface, amid about the C-terminal braid (Fig. 3, B and C) (28). Both the N and C termini point apparent from the polymeric helix, so this polymer anatomy could be accommodated at any point in a protein sequence. The intersubunit interactions in the TEL-SAM polymer are actual abiding with a break connected Kd ~2 nM, implying that the alternation may be of biological appliance (27). Moreover, polymer-blocking mutations (at interface residues Ala93 and Val112) (Fig. 3B) block TEL repression in corpuscle culture, acerb suggesting that the polymeric anatomy is capital for the transcriptional-repression action of TEL (29). SAM polymerization may accommodate a apparatus for overextension of a area of repression forth the chromatin, although there is still no absolute affirmation of this (27).
Tyrosine kinases can be activated by oligomerization, so it is not adamantine to see how the adapter of a polymerization bore to a kinase domain, as begin in the oncogenic TEL-SAM fusions, could advance to basal kinase activation (30). The adventure is not so simple, however. Back the role of polymerization in the transformation action of the TEL-NTRK3 bubble (also alleged ETV6-NTRK3 or EN) (31) is examined, both SAM area bounden interfaces are begin to be capital for abounding EN transformation activity. EN mutants absolute mutations that change berserk amino acerbic residues to hydrophilic ones aural the polymerization interface (A93D and V112E or V112R) abort to self-associate, do not become tyrosine phosphorylated, and do not transform NIH 3T3 cells. Moreover, gel-filtration chromatography and electron microscopy abstracts advance that, although the EN bubble polymerizes to anatomy college adjustment complexes both in vitro and in vivo, EN variants with polymer-blocking mutations aural their SAM domains are abundantly monomeric in solution. Dimerization abandoned is not acceptable to transform NIH 3T3 cells. Back the SAM area in the bubble was replaced by an FKBP-binding domain, a chemically inducible dimerization motif, the chimeric protein became tyrosine phosphorylated aloft dimerization, but it did not abet NIH 3T3 corpuscle transformation. Abandoned brief MEK1 activation, cyclin D1 up-regulation, and AKT activation were empiric in these beef afterwards the accession of the dimerization inducer, which suggests that clashing EN, chemically induced FKBP-NTRK3 dimers abridgement the adeptness to constitutively actuate the Ras-MAPK and phosphatidylinositol 3-kinase (PI3K)–AKT cascades. Although the abiding coexpression of the V112E and A93D EN-SAM mutants in NIH 3T3 beef led to heterodimerization, tyrosine kinase activation was not empiric and the beef were not transformed. These allegation betoken that SAM area polymerization in these oncogenic fusions charge do added than artlessly actualize the aing adjacency of tyrosine kinase domains.
The key role of polymerization in corpuscle transformation by TEL-SAM oncogenic fusions suggests that one accessible ameliorative action would be to acquisition reagents that could block TEL-SAM polymerization. Abandoned SAM domains should be able to bind to the EN chimeras and could thereby block corpuscle transformation (31, 32). Indeed, back either wild-type or poylmer-blocking aberrant SAM domains were bidding in NIH 3T3 cells, EN-mediated morphological transformation and bendable agar antecedents accumulation were reduced. Beef cogent both the abandoned SAM and EN chimeras showed a bargain adeptness to anatomy tumors in nude mice compared with beef cogent the EN bubble only. This indicates that the SAM area may act as a ascendant abrogating regulator of polymerization-mediated kinase activation and corpuscle transformation by the EN chimera. Thus, authoritative corpuscle transformation by targeting the polymerization interface adeptness serve as a abeyant ameliorative strategy. However, polymer disruptors could additionally affect the transcriptional repression action of wild-type TEL, which acts as a bump suppressor.
The ETS ancestors SAM domain–containing proteins Yan, Mae, and Pointed-P2 (Pnt-P2) are additionally circuitous in transcriptional adjustment during the development of Drosophila eyes (Fig. 4A) (33). Yan is a transcriptional repressor (13, 34) and Pointed-P2 is a transcriptional activator (35, 36), and both are accountable to adjustment by the MAP kinase Rolled. Aloft dispatch of the Sevenless or epidermal advance agency (EGF) receptors and activation of the Ras-MAP kinase pathway, Yan becomes abeyant and Pnt-P2 becomes active, aesthetic the archetype of ahead repressed genes.
Mae adjustment of Yan and Pnt-P2 through SAM area interactions. (A) Aloft the activation of the receptor tyrosine kinase (RTK) pathway, through the guanosine triphosphatase RAS and the mitogen-activated protein kinase (MAPK) cascade, MAP kinase Rolled becomes dual-phosphorylated and translocates to the nucleus. In the nucleus, activated Rolled phosphorylates two ETS ancestors archetype factors: Yan, a archetype repressor; and Pnt-P2, a archetype activator. Phosphorylation of Yan after-effects in aishment of its repressor action and its about-face to the cytoplasm. In contrast, phosphorylated Pnt-P2 becomes an alive archetype activator, which again stimulates the announcement of adverse genes. Moreover, the phosphorylation of Yan and Pnt-P2 is adapted by Mae through interactions advised by the SAM domains of Mae, Yan, and Pnt-P2 (B) Overall anatomy of Yan- and Mae-SAM domains compared with the Yan-SAM polymer model. Yan-SAM and Mae-SAM are apparent in dejected and violet, respectively. ML apparent residues are black green, and EH apparent residues are black red. (C) The accumulation of polymeric Yan on DNA by its SAM area alternation makes its key phosphorylation site, Ser127, aloof to the MAP kinase Rolled. Depolymerization of Yan by Mae exposes this phosphorylation armpit to Rolled.
Yan was articular through a abiogenetic awning as a abrogating regulator of R7 photoreceptor development acting abnormally to the Sevenless–Ras–MAP kinase alleyway (13). It functions as a repressor of ETS-responsive genes. Phosphorylation of Yan by the MAP kinase Rolled leads to inactivation and consign from the basis (34). The best important phosphorylation site, Ser127, is actual aing to the C aals of the Yan SAM domain. Although Yan becomes abeyant aloft phosphorylation, the transcriptional activator Pnt-P2 is activated back phosphorylated by Rolled. Pnt-P2 contains an N-terminal SAM area and C-terminal ETS DNA bounden area (35, 37).
Another basal of this arresting transduction alleyway is alleged Mae (modulator of the action of ETS) (17). Mae is capital for the accustomed development and action of Drosophila and is appropriate in vivo for accustomed signaling of the EGF receptor. Mae is additionally appropriate for Rolled phosphorylation of Yan. Mae contains a SAM area that binds to the SAM domains of both Yan and Pnt-P2. Rolled additionally binds to Mae, suggesting that Mae recruits the kinase to the armpit of action, possibly in concert with some array of conformational change activated on Yan by Mae. Mae additionally inhibits DNA bounden by Yan, although the apparatus is cryptic (17).
Additional acumen into this circuitous authoritative arrangement came from structure-based studies of Yan-SAM. Like its beastly ortholog, the TEL-SAM domain, the abandoned SAM area of Yan forms a head-to-tail polymer (Fig. 4B), although the alternation amid anniversary subunit (Kd ~ 11 μM) is abundant weaker than that of the TEL-SAM domain. Yan variants address mutations that block polymerization do not repress archetype as calmly as does wild-type Yan, advertence that the adeptness to polymerize is capital for Yan action (18).
Mae causes depolymerization of Yan, absolute a new apparatus for authoritative transcriptional repression by Yan. The clear anatomy of interacting Mae and Yan-SAM domains explains in detail how Mae inhibits polymerization of Yan. The Mae-SAM area interacts through its ML apparent with the EH apparent of Yan-SAM, authoritative the EH apparent bare for polymer formation. The bounden approach of Mae about altogether mimics the bounden approach in polymers of Yan-SAM domains. However, the affection of the Mae-SAM area for bounden to the Yan-SAM area is ~1000 times as aerial as that of Yan-SAM for bounden to itself, so Mae is able to attempt finer with Yan polymer formation.
That Mae inhibits polymerization of Yan additionally suggests an another apparatus by which Mae can facilitate Yan phosphorylation. The key phosphorylation armpit on Yan, Ser127, is actual aing to the SAM area and would accordingly best acceptable be aloof to the kinase in the polymer. Depolymerization may accordingly enhance admission of the kinase to the phosphorylation armpit (Fig. 4C). Thus, by benign depolymerization of Yan, Mae could accept a able role in authoritative Yan function. Moreover, Yan represses the archetype of Mae (38), so that inhibition of Yan would advance to added accumulation of Mae. Thus, the arrangement is allegedly advised for accessory down-regulation of Yan and up-regulation of Mae. Thus, depolymerization of Yan by Mae represents a apparatus of transcriptional ascendancy that sensitizes Yan for adjustment by receptor activation (18).
Polycomb accumulation (PcG) proteins are accepted transcriptional repressors capital for advancement the archetype arrangement of key authoritative genes throughout development in abounding bacilli (39). They are best accepted as repressors that bind Hox gene announcement forth the anterior-posterior beastly anatomy axis. They are about classified not by their conserved domains or structural motifs, but by their accepted function. PcG proteins, alive calm in ample complexes, adapt chromatin of the ambition gene to advance repressed states for continued periods of time and through abounding corpuscle capacity (40). Two aloft PcG complexes accept been characterized in Drosophila, alleged the ESC-E(Z) circuitous (41–43) and Polycomb backbreaking circuitous 1 (PRC1) (44–46). The amount subunits of both complexes are additionally conserved in mammals (45). Both antiseptic fly antecedent PRC1, and recombinant, reconstituted PRC1 circuitous can block nucleosome adjustment by SWI/SNF chromatin adjustment circuitous in vitro, possibly by breeding a college adjustment chromatin anatomy adverse to gene archetype (44, 46).
SAM domains are begin in several Drosophila Polycomb accumulation proteins and their beastly relatives. Information about the anatomy and action of PcG SAM domains comes abundantly from studies on Polyhomeotic (Ph) and Sex adjust on midleg (Scm), which both accommodate C-terminal SAM domains (47) (Fig. 1).
Both Ph and Scm are begin in PRC1, although Scm is begin in substoichiometric amounts and is not advised to be one of the amount apparatus of PRC1 (44). Nevertheless, aggrandize two-hybrid and in vitro protein-protein alternation assays actualization that SAM domains of Ph and Scm collaborate both with themselves and with anniversary other. Moreover, Ph and Scm both localize calm at Drosophila polytene chromosome sites, implying that they adeptness action calm to repress archetype (47).
The Ph-SAM area forms a polymer, and the polymer clear anatomy has been solved. The polymer architectonics is actual agnate to that of TEL-SAM, that is, a left-handed, head-to-tail circling polymer (48). The polymer subunits collaborate through agnate ML and EH surfaces. The intersubunit interactions are able (like those of TEL-SAM) with a Kd of 190 nM. The Scm-SAM area forms a polymer that has a agnate architectonics to that of polymers formed for TEL-SAM or Ph-SAM (49). That TEL, Ph, and Scm actualization basal arrangement affection and allotment no added accepted domains, yet accomplish actual agnate polymer structures, lends added weight to the altercation that these polymers are biologically accordant and comedy important roles in transcriptional repression.
In vivo studies of the role of Scm-SAM in PcG repression added abutment a biological action for the Scm-SAM polymer and the alternation of the Scm- and Ph-SAM domains (50). In abiogenetic accomplishment assays, a accumulating of Scm variants absolute accidental SAM area mutations were alien to an Scm-null strain. Abandoned those mutants that retained the adeptness to self-associate [as absolute by two-hybrid and GST (glutathione S-transferase) pull-down assays] abiding accumulation of abundant and phenotypically accustomed flies (50). The mutants that did not self-associate mapped to the ML and EH surfaces of the Scm-SAM area and acceptable block polymerization. This was added embodied by PcG loss-of-function phenotypes acquired by overexpression of an abandoned Scm-SAM area in vivo. Overexpression of the Scm-SAM area apparently interferes with anatomic polymer accumulation by the affection protein. PcG repression can action over continued distances. Although the apparatus of all-embracing repression is not known, it seems accessible that polymerization of PcG forth the chromosome could accept a role (48).
The agnate beastly logs of several fly PcG proteins accept been identified. Bodies accept assorted versions of anniversary PcG gene. For example, three beastly logs of Drosophila Ph accept been articular so far: hPh1, hPh2 (51), and hPh3 (45). They action in repression complexes that arrest SWI/SNF adjustment of nucleosomal arrays and may be important for transcriptional repression in vivo. The SAM domains of hPh1 and hPh2 arbitrate self-association, conceivably by polymerization (51). Despite the area alteration of these beastly Ph logs, they all accommodate SAM domains, advertence the accent of SAM domains to Ph function.
The aboriginal Polycomb accumulation protein apparent in Caenorhabditis elegans, SOP-2, was afresh abandoned in a abiogenetic awning for suppressors of the homeobox gene pal-1 (52). Arrangement comparisons to added PcG proteins appear that the abandoned conserved area in SOP-2 is the SAM domain, which is carefully accompanying to the SAM domains of Drosophila PcG proteins. Despite the abridgement of added arrangement similarity, the attendance of a SAM area in SOP-2 suggests that this C. elegans agency may additionally self-associate, acceptance it to potentially comedy the aforementioned role as its counterparts in the fly.
A bond amid the SAM area of the PcG accumulation and that of ETS proteins was accustomed by the award that the beastly PcG protein log, L(3)MBT [lethal(3)malignant academician bump protein], and TEL collaborate through their SAM domains (53). Moreover, announcement of the h- L(3)MBT SAM area enhances the ability of transcriptional repression advised by TEL, advertence that the alternation is functional. These after-effects advance that accepted transcriptional repression accouterment can be recruited, by SAM area association, to alone ambition genes through the DNA bounden specificity able by the ETS ancestors protein TEL.
The acceptable acceptance that SAM domains are protein-protein alternation motifs was afresh angry on its arch by assignment on Smaug and its ancestors (54, 55). Smaug is appropriate for the enactment of a morphogen acclivity in the developing antecedent through repression of Nanos mRNA adaptation in the aggregate cytoplasm. Smaug binds to an RNA stem-loop consisting of a 9–base brace braid capped by a five-ribonucleotide bend aural the adaptation ascendancy aspect of the nanos mRNA 3′-untranslated region. This alternation appears to be all-important for the able action of Smaug because mutations in the bend abate the repression of Nanos adaptation (56–58). The RNA bounden arena of Smaug corresponds to its SAM area (54, 55). The clear anatomy of a Smaug RNA bounden region, absolute both a SAM and a PHAT (pseudo-HEAT echo akin topology) domain, shows that Smaug-SAM conforms to the accord SAM area architecture. One audible affection of Smaug-SAM is the actualization of a array of absolutely answerable residues on its apparent (Fig. 5). A database chase appear a ancestors of Smaug logs from aggrandize to human, all of which accept about the aforementioned RNA bounden specificity as fly Smaug, alike admitting their arrangement affection is belted to the SAM domain. Thus, both structural and arrangement attention appraisal advance that the SAM area of Smaug is the RNA bounden motif. A aggrandize three-hybrid appraisal was acclimated to baddest Smaug mutants that can still bind to RNA. This awning abandoned variants with apparent substitutions about everywhere except the electropositive face of the SAM domain. Engineered substitutions in the conserved basal residues of the electropositive face bargain RNA bounden affection (54). The abandoned SAM area of Vts1, a aggrandize Smaug log, binds to non–stem-loop RNA with aerial affinity, commensurable to that of the affection Vts1 protein. SAM-mediated RNA binding, articular through a aggregate of structural, biochemical, and abiogenetic studies on Smaug and its relatives, represents a new approach of SAM area action. Conceivably SAM domains may abide to accept added new faces apparent (7, 59).
Crystal anatomy of Smaug RNA bounden arena and the abeyant RNA bounden apparent on Smaug-SAM. The SAM area is black pink, and the PHAT area is black white. Residues that are capital for RNA bounden are accent in blue.
The cardinal of SAM domains in an beastly about correlates with its complexity.
Not all SAM self-associations aftereffect in polymer formation. Several SAM area proteins circuitous in aggrandize MAP kinase cascades additionally assume to anatomy bankrupt oligomers.
In the fission aggrandize Sschizosaccaromyces pombe, pheromone-induced beastly adverse is controlled via a MAPK alleyway that includes the arch proteins Ste4 and Byr2 (60, 61). Byr2 is a MAPK kinase kinase that is activated by interactions with both Ras1 and Ste4. The SAM area of Byr2 has been apparent to bind to the N-terminal 160 amino acids of Ste4, a arena absolute a SAM area followed anon by a leucine attachment (Ste4-LZ) domain. This alternation is capital for able signaling (62). The abandoned SAM domains of Byr2 and Ste4 are both monomeric and bind to anniversary added in a 1:1 stoichiometry with Kd ~ 56 μM (63). However, back the leucine attachment area is included with Ste4-SAM, it forms a 3:1 Ste4-LZ-SAM:Byr2-SAM circuitous with abundant college affection (Kd ~ 19 nM) (63). Systematic mutagenesis of the apparent residues on both Byr2- and Ste4-SAM mapped the bounden interface amid them to the ML apparent of Byr2-SAM and the EH apparent of Ste4-SAM, as did agnate appraisal of the alternation amid Mae-SAM and Yan-SAM (64). This suggests that SAM domains can use agnate surfaces for the accumulation of altered types of oligomeric states. How this SAM alternation regulates action of the Byr2 protein kinase charcoal unclear.
Structural and biochemical studies accept additionally been done with Ste11 and Ste50 in Saccharomyces cerevisiae, which are orthologs of Byr2 and Ste4, appropriately (65, 66). NMR band-aid structures of the Ste11 and Ste50 SAM domains actualization structures agnate to those of added SAM domains (67, 68). Ste11-SAM forms a anemic dimer in band-aid with Kd ~ 0.5 mM (68). Again, the interface was mapped to EH and ML surfaces by comparing the chemical-shift changes amid concentrated and adulterated solutions of Ste11-SAM. A aggregate of actinic cross-linking and apparent plasmon resonance abstracts approved that SAM domains of Ste11 and Ste50 anatomy a high-affinity heterodimer (Kd ~ 71 nM) (67). Preliminary mutagenesis studies showed that one of the Ste11-SAM ML apparent mutants fails to collaborate with Ste50-SAM, implying that Ste11-SAM adeptness use its ML apparent to bind to the EH apparent of Ste50-SAM (67, 68).
Members of the Eph receptor tyrosine kinase ancestors of proteins calm with their activating ligands, termed ephrins, are circuitous in contact-mediated axon guidance, axon fasciculation, vascular arrangement assembly, capillary morphogenesis, and angiogenesis. Alternation of Eph receptor proteins with ephrins can actuate bidirectional signaling pathways, frequently consistent in abhorrent cell-cell signaling (69).
SAM domains are begin at the C aals of all the accepted Eph proteins (3). Several crystallographic and NMR studies accept yielded approved SAM area structures (70–73). Clear structures of the EphA4-SAM area and the EphB2-SAM area appear abeyant oligomeric forms. In the case of the EphA4-SAM, a ample interface was articular that could represent a dimer anatomy (73). In the case of EphB2-SAM, two ample interfaces may advance to a polymeric anatomy (72). Although in both cases there are affidavit to anticipate that these interfaces are added than clear contacts, self-association in band-aid is consistently absolutely aged with these SAM domains (Kd > 1 mM). However, alike anemic interactions can advance to advantageous associations back proteins are tethered to a membrane, or back they are amassed by ligand interactions. It is accordingly accessible that the SAM domains comedy an accessory role to the absorption action all-important for signaling. Nevertheless, it is actual difficult to affirm or abjure the accent of such anemic interactions, so these oligomers abide hypothetical. Surprisingly, abatement of EphA4-SAM area does not agitate Eph signaling, abstinent either as kinase action of EphA4 kinase or absorption and ligand activation (74). A Phe-to-Tyr alteration at position 928 aural the SAM domain, however, acquired an access in ectopic consecration of after protrusions back compared with wild-type EphA4, suggesting that Tyr928 may abnormally adapt EphA4 action (75).
SAM domains are additionally present in Brand ancestors proteins, which are awful accomplished in the postsynaptic body (PSD), acting as scaffolds to adapt accumulation of postsynaptic proteins (76). The SAM area of Shank1 self-associates and may accept a role acclimation the PSD (77).
In accession to interactions with the kinases discussed previously, SAM domains additionally collaborate with added proteins that abridgement SAM domains. For example, the SAM area of BAR (bifunctional apoptosis regulator), which can adapt both acquired and built-in apoptosis pathways, binds the corpuscle afterlife suppressors Bcl-2 and Bcl-XL (78). Moreover, BAR suppresses BAX-induced apoptosis admitting a SAM domain–dependent apparatus in both aggrandize and beastly cells. However, the atomic capacity of these activities abide unclear.
The SAM area of ETS-2 is both all-important and acceptable for the bounden of ETS-2 to the C-terminal area of CREB-binding protein [CBP-SID (steroid receptor coactivator alternation domain)]. Moreover, this bounden arena on ETS-2–SAM was narrowed bottomward to its fifth helix. Corpuscle adeptness assays showed that this alternation is important for ETS-2–mediated transactivation (79).
As discussed above, RTK-Ras-MAPK pathway–mediated phosphorylation of Ser127 on Yan, a balance aloof 10 amino acids abroad from the C aals of the Yan-SAM domain, abrogates Yan’s transcriptional repressor action and facilitates Crm1-adapted about-face out of the basis (34, 80). Conversely, phosphorylation of a balance actual aing to the Pnt-P2 SAM domain, Thr151, by the aforementioned alleyway increases transcriptional activation by PNT-P2 (35, 37). Thus, this accepted alleyway of adjustment can accept audible after consequences.
Two observations articulation SUMO (small unbiquitin-like modifier) anon to SAM domains. The ETS ancestors archetype repressor TEL interacts with UBC9 (81), a affiliate of the SUMO conjugating enzymes, through its SAM domain. This alternation leads to the SUMOylation of Lys99 in TEL-SAM (82), appropriately abbreviating the repression action of TEL. Alteration of Lys99 acquired decreased nuclear export. Unexpectedly, SAM area polymerization seems to be important for the SUMOylation acknowledgment (29). The acumen is still a mystery. Interestingly, SUMOylation has absolutely adverse furnishings on C. elegans PcG protein SOP-2, in which case, SUMOylation of SOP-2 through the alternation amid UBC9 and the SOP-2 SAM area is appropriate for its localization to nuclear bodies in vivo and for its physiological repression of Hox genes (83).
In the decade back Ponting’s identification of SAM domains from 14 proteins, abounding added proteins accept been articular with SAM domains. Ponting’s anticipation that SAM domains adeptness be circuitous in protein-protein interactions accepted prescient. SAM domains can collaborate with themselves, bind to added SAM domains, bind to non–SAM area proteins such as kinases or SUMO conjugating enzyme, and can alike bind to RNA. We now accept a abundant compassionate of SAM area action in a array of systems. High-resolution structures of – and heterotypic SAM area interactions accept abundantly facilitated our attempts to annotate the atomic apparatus of several arresting transduction pathways and gene adjustment circuits that accommodate SAM domain–containing proteins. Nevertheless, we accept apparently abandoned aching the apparent of SAM area functions and alternation modes, and there are acceptable roles for SAM domains that abide to be discovered. For example, p73, a log of the bump suppressor p53, was afresh begin to collaborate with lipids by in vitro biochemical assays, although the biological acceptation of this award still charcoal cryptic (84). At present, it is adamantine to see how these another SAM area functions can be deciphered after accomplishing the adamantine assignment of added biological, biochemical, and biophysical assuming of alone systems.
C. P. Ponting, SAM: A atypical burden in aggrandize antiseptic and Drosophila polyhomeotic proteins. Protein Sci. 4, 1928–1930 (1995). pmid:8528090
J. Schultz, C. P. Ponting, K. Hofmann, P. Bork, SAM as a protein alternation area circuitous in adorning regulation. Protein Sci. 6, 249–253 (1997). pmid:9007998
T. Pawson, P. Nash, Accumulation of corpuscle authoritative systems through protein alternation domains. Science 300, 445–452 (2003). pmid:12702867
T. Pawson, Specificity in arresting transduction: From phosphotyrosine-SH2 area interactions to circuitous cellular systems. Corpuscle 116, 191–203 (2004). pmid:14744431
B. Schaffhausen, SH2 area anatomy and function. Biochim. Biophys. Acta 1242, 61–75 (1995). pmid:7542925
A. Zarrinpar, R. P. Bhattacharyya, W. A. Lim, The anatomy and action of proline acceptance domains. Sci. STKE 2003, re8 (2003). pmid:12709533
C. A. Kim, J. U. Bowie, SAM domains: Uniform structure, assortment of function. Trends Biochem. Sci. 28, 625–628 (2003). pmid:14659692
B. J. Graves, M. E. Gillespie, L. P. McIntosh, DNA bounden by the ETS domain. Nature 384, 322 (1996). pmid:8934514
A. D. Sharrocks, The ETS-domain archetype agency family. Nat. Rev. Mol. Corpuscle Biol. 2, 827–837 (2001). pmid:11715049
D. K. Watson, M. J. McWilliams-Smith, M. F. Nunn, P. H. Duesberg, S. J. O’Brien, T. S. Papas, The ets arrangement from the transforming gene of aerial erythroblastosis virus, E26, has different domains on beastly chromosomes 11 and 21: Both loci are transcriptionally active. Proc. Natl. Acad. Sci. U.S.A. 82, 7294–7298 (1985). pmid:2997781
N. Sacchi, D. K. Watson, A. H. Guerts van Kessel, A. Hagemeijer, J. Kersey, H. D. Drabkin, D. Patterson, T. S. Papas, Hu-ets-1 and Hu-ets-2 genes are antipodal in astute leukemias with (4;11) and (8;21) translocations. Science 231, 379–382 (1986). pmid:3941901
T. R. Golub, G. F. Barker, M. Lovett, D. G. Gilliland, Admixture of PDGF receptor beta to a atypical ets-like gene, tel, in abiding myelomonocytic leukemia with t(5;12) chromosomal translocation. Corpuscle 77, 307–316 (1994). pmid:8168137
Z. C. Lai, G. M. Rubin, Abrogating ascendancy of photoreceptor development in Drosophila by the artefact of the yan gene, an ETS area protein. Corpuscle 70, 609–620 (1992). pmid:1505027
C. M. Slupsky, L. N. Gentile, L. W. Donaldson, C. D. Mackereth, J. J. Seidel, B. J. Graves, L. P. McIntosh, Anatomy of the Ets-1 acicular area and mitogen-activated protein kinase phosphorylation site. Proc. Natl. Acad. Sci. U.S.A. 95, 12129–12134 (1998). pmid:9770451
J. J. Seidel, B. J. Graves, An ERK2 advancing armpit in the Acicular area distinguishes a subset of ETS archetype factors. Genes Dev. 16, 127–137 (2002). pmid:11782450
M. Kasten, A. Giordano, Cdk10, a Cdc2-related kinase, accumulation with the Ets2 archetype agency and modulates its transactivation activity. Oncogene 20, 1832–1838 (2001). pmid:11313931
D. A. Baker, B. Mille-Baker, S. M. Wainwright, D. Ish-Horowicz, N. J. Dibb, Mae mediates MAP kinase phosphorylation of Ets archetype factors in Drosophila. Nature 411, 330–334 (2001). pmid:11357138
F. Qiao, H. Song, C. A. Kim, M. R. Sawaya, J. B. Hunter, M. Gingery, I. Rebay, A. J. Courey, J. U. Bowie, Derepression by depolymerization: Structural insights into the adjustment of Yan by Mae. Corpuscle 118, 163–173 (2004). pmid:15260987
H. Poirel, C. Oury, C. Carron, E. Duprez, Y. Laabi, A. Tsapis, S. P. Romana, M. Mauchauffe, M. Le Coniat, R. Berger, J. Ghysdael, O. A. Bernard, The TEL gene products: Nuclear phosphoproteins with DNA bounden properties. Oncogene 14, 349–357 (1997). pmid:9018121
A. Buijs, S. Sherr, S. van Baal, S. van Bezouw, D. van der Plas, A. Geurts van Kessel, P. Riegman, R. Lekanne Deprez, E. Zwarthoff, A. Hagemeijer, G. Grosveld, About-face (12;22) (p13;q11) in myeloproliferative disorders after-effects in admixture of the ETS-like TEL gene on 12p13 to the MN1 gene on 22q11. Oncogene 10, 1511–1519 (1995) [published absurdity appears in Oncogene 11, 809 (1995)]. pmid:7731705
P. Papadopoulos, S. A. Ridge, C. A. Boucher, C. Stocking, L. M. Wiedemann, The atypical activation of ABL by admixture to an ets-related gene, TEL. Cancer Res. 55, 34–38 (1995). pmid:7805037
J. M. Ho, B. K. Beattie, J. A. Squire, D. A. Frank, D. L. Barber, Admixture of the ets archetype agency TEL to Jak2 after-effects in basal Jak-Stat signaling. Blood 93, 4354–4364 (1999). pmid:10361134
T. R. Golub, G. F. Barker, S. K. Bohlander, S. W. Hiebert, D. C. Ward, P. Bray-Ward, E. Morgan, S. C. Raimondi, J. D. Rowley, D. G. Gilliland, Admixture of the TEL gene on 12p13 to the AML1 gene on 21q22 in astute lymphoblastic leukemia. Proc. Natl. Acad. Sci. U.S.A. 92, 4917–4921 (1995). pmid:7761424
F. Salomon-Nguyen, V. Della-Valle, M. Mauchauffe, M. Busson-Le Coniat, J. Ghysdael, R. Berger, O. A. Bernard, The t(1;12)(q21;p13) about-face of beastly astute myeloblastic leukemia after-effects in a TEL-ARNT fusion. Proc. Natl. Acad. Sci. U.S.A. 97, 6757–6762 (2000). pmid:10829078
T. R. Golub, T. McLean, K. Stegmaier, M. Carroll, M. Tomasson, D. G. Gilliland, The TEL gene and beastly leukemia. Biochim. Biophys. Acta 1288, M7–M10 (1996). pmid:8764840
C. Jousset, C. Carron, A. Boureux, C. T. Quang, C. Oury, I. Dusanter-Fourt, M. Charon, J. Levin, O. Bernard, J. Ghysdael, A area of TEL conserved in a subset of ETS proteins defines a specific oligomerization interface capital to the mitogenic backdrop of the TEL-PDGFR beta oncoprotein. EMBO J. 16, 69–82 (1997). pmid:9009269
C. A. Kim, M. L. Phillips, W. Kim, M. Gingery, H. H. Tran, M. A. Robinson, S. Faham, J. U. Bowie, Polymerization of the SAM area of TEL in leukemogenesis and transcriptional repression. EMBO J. 20, 4173–4182 (2001). pmid:11483520
H. H. Tran, C. A. Kim, S. Faham, M. C. Siddall, J. U. Bowie, Native interface of the SAM area polymer of TEL. BMC Struct. Biol. 2, 5–10 (2002). pmid:12193272
L. D. Wood, B. J. Irvin, G. Nucifora, K. S. Luce, S. W. Hiebert, Baby ubiquitin-like modifier alliance regulates nuclear consign of TEL, a accepted bump suppressor. Proc. Natl. Acad. Sci. U.S.A. 100, 3257–3262 (2003). pmid:12626745
T. R. Golub, A. Goga, G. F. Barker, D. E. Afar, J. McLaughlin, S. K. Bohlander, J. D. Rowley, O. N. Witte, D. G. Gilliland, Oligomerization of the ABL tyrosine kinase by the Ets protein TEL in beastly leukemia. Mol. Cell. Biol. 16, 4107–4116 (1996). pmid:8754809
C. E. Tognon, C. D. Mackereth, A. M. Somasiri, L. P. McIntosh, P. H. Sorensen, D. Stapleton, I. Balan, T. Pawson, F. Sicheri, Mutations in the SAM area of the ETV6-NTRK3 chimeric tyrosine kinase block polymerization and transformation activity. Mol. Cell. Biol. 24, 4636–4650 (2004). pmid:15143160
C. F. Chuang, C. I. Bargmann, A Toll-interleukin 1 echo protein at the synapse specifies agee odorant receptor announcement via ASK1 MAPKKK signaling. Genes Dev. 19, 270–281 (2005). pmid:15625192
I. Rebay, Keeping the receptor tyrosine kinase signaling alleyway in check: Lessons from Drosophila. Dev. Biol. 251, 1–17 (2002). pmid:12413894
I. Rebay, G. M. Rubin, Yan functions as a accepted inhibitor of adverse and is abnormally adapted by activation of the Ras1/MAPK pathway. Corpuscle 81, 857–866 (1995). pmid:7781063
E. M. O’Neill, I. Rebay, R. Tjian, G. M. Rubin, The activities of two Ets-related archetype factors appropriate for Drosophila eye development are articulate by the Ras/MAPK pathway. Corpuscle 78, 137–147 (1994). pmid:8033205
C. Klambt, The Drosophila gene acicular encodes two ETS-like proteins which are circuitous in the development of the midline glial cells. Development 117, 163–176 (1993). pmid:8223245
D. Brunner, K. Ducker, N. Oellers, E. Hafen, H. Scholz, C. Klambt, The ETS area protein pointed-P2 is a ambition of MAP kinase in the sevenless arresting transduction pathway. Nature 370, 386–389 (1994). pmid:8047146
P. Vivekanand, T. L. Tootle, I. Rebay, MAE, a bifold regulator of the EGFR signaling pathway, is a ambition of the Ets archetype factors PNT and YAN. Mech. Dev. 121, 1469–1479 (2004). pmid:15511639
V. Orlando, Polycomb, epigenomes, and ascendancy of corpuscle identity. Corpuscle 112, 599–606 (2003). pmid:12628181
N. J. Francis, R. E. Kingston, Mechanisms of transcriptional memory. Nat. Rev. Mol. Corpuscle Biol. 2, 409–421 (2001). pmid:11389465
J. Muller, C. M. Hart, N. J. Francis, M. L. Vargas, A. Sengupta, B. Wild, E. L. Miller, M. B. O’Connor, R. E. Kingston, J. A. Simon, Histone methyltransferase action of a Drosophila Polycomb accumulation repressor complex. Corpuscle 111, 197–208 (2002). pmid:12408864
C. A. Jones, J. Ng, A. J. Peterson, K. Morgan, J. Simon, R. S. Jones, The Drosophila esc and E(z) proteins are absolute ally in polycomb group-mediated repression. Mol. Cell. Biol. 18, 2825–2834 (1998). pmid:9566901
J. Ng, C. M. Hart, K. Morgan, J. A. Simon, A Drosophila ESC-E(Z) protein circuitous is audible from added polycomb accumulation complexes and contains covalently adapted ESC. Mol. Cell. Biol. 20, 3069–3078 (2000). pmid:10757791
Z. Shao, F. Raible, R. Mollaaghababa, J. R. Guyon, C. T. Wu, W. Bender, R. E. Kingston, Stabilization of chromatin anatomy by PRC1, a Polycomb complex. Corpuscle 98, 37–46 (1999). pmid:10412979
S. S. Levine, A. Weiss, H. Erdjument-Bromage, Z. Shao, P. Tempst, R. E. Kingston, The amount of the polycomb backbreaking circuitous is compositionally and functionally conserved in flies and humans. Mol. Cell. Biol. 22, 6070–6078 (2002). pmid:12167701
N. J. Francis, A. J. Saurin, Z. Shao, R. E. Kingston, Reconstitution of a anatomic amount polycomb backbreaking complex. Mol. Corpuscle 8, 545–556 (2001). pmid:11583617
A. J. Peterson, M. Kyba, D. Bornemann, K. Morgan, H. W. Brock, J. Simon, A area aggregate by the Polycomb accumulation proteins Scm and ph mediates heterotypic and typic interactions. Mol. Cell. Biol. 17, 6683–6692 (1997). pmid:9343432
C. A. Kim, M. Gingery, R. M. Pilpa, J. U. Bowie, The SAM area of polyhomeotic forms a circling polymer. Nat. Struct. Biol. 9, 453–457 (2002). pmid:11992127
C. A. Kim, J. U. Bowie, abstruse data.
A. J. Peterson, D. R. Mallin, N. J. Francis, C. S. Ketel, J. Stamm, R. K. Voeller, R. E. Kingston, J. A. Simon, Requirement for adjust on midleg protein interactions in Drosophila polycomb accumulation repression. Genetics 167, 1225–1239 (2004). pmid:15280237
M. J. Gunster, D. P. Satijn, K. M. Hamer, J. L. den Blaauwen, D. de Bruijn, M. J. Alkema, M. van Lohuizen, R. van Driel, A. P. Otte, Identification and assuming of interactions amid the bearcat polycomb-group protein BMI1 and beastly logs of polyhomeotic. Mol. Cell. Biol. 17, 2326–2335 (1997). pmid:9121482
H. Zhang, R. B. Azevedo, R. Lints, C. Doyle, Y. Teng, D. Haber, S. W. Emmons, Global adjustment of Hox gene announcement in C. elegans by a SAM area protein. Dev. Corpuscle 4, 903–915 (2003). pmid:12791274
P. Boccuni, D. MacGrogan, J. M. Scandura, S. D. Nimer, The beastly L(3)MBT polycomb accumulation protein is a transcriptional repressor and interacts physically and functionally with TEL (ETV6). J. Biol. Chem. 278, 15412–15420 (2003). pmid:12588862
T. Aviv, Z. Lin, S. Lau, L. M. Rendl, F. Sicheri, C. A. Smibert, The RNA-binding SAM area of Smaug defines a new ancestors of post-transcriptional regulators. Nat. Struct. Biol. 10, 614–621 (2003). pmid:12858164
J. B. Green, C. D. Gardner, R. P. Wharton, A. K. Aggarwal, RNA acceptance via the SAM area of Smaug. Mol. Corpuscle 11, 1537–1548 (2003). pmid:12820967
A. Dahanukar, J. A. Walker, R. P. Wharton, Smaug, a atypical RNA-binding protein that operates a translational about-face in Drosophila. Mol. Corpuscle 4, 209–218 (1999). pmid:10488336
C. A. Smibert, J. E. Wilson, K. Kerr, P. M. Macdonald, smaug protein represses adaptation of unlocalized nanos mRNA in the Drosophila embryo. Genes Dev. 10, 2600–2609 (1996). pmid:8895661
C. A. Smibert, Y. S. Lie, W. Shillinglaw, W. J. Henzel, P. M. Macdonald, Smaug, a atypical and conserved protein, contributes to repression of nanos mRNA adaptation in vitro. RNA 5, 1535–1547 (1999). pmid:10606265
T. M. Hall, SAM break its stereotype. Nat. Struct. Biol. 10, 677–679 (2003). pmid:12942139
M. M. Barr, H. Tu, L. Van Aelst, M. Wigler, Identification of Ste4 as a abeyant regulator of Byr2 in the beastly acknowledgment alleyway of Schizosaccharomyces pombe. Mol. Cell. Biol. 16, 5597–5603 (1996). pmid:8816472
H. Tu, M. Barr, D. L. Dong, M. Wigler, Assorted authoritative domains on the Byr2 protein kinase. Mol. Cell. Biol. 17, 5876–5887 (1997). pmid:9315645
P. Bauman, C. F. Albright, Anatomic appraisal of domains in the Byr2 kinase. Biochimie 80, 621–625 (1998). pmid:9810469
R. Ramachander, C. A. Kim, M. L. Phillips, C. D. Mackereth, C. D. Thanos, L. P. McIntosh, J. U. Bowie, Oligomerization-dependent affiliation of the SAM domains from Schizosaccharomyces pombe Byr2 and Ste4. J. Biol. Chem. 277, 39585–39593 (2002). pmid:12171939
R. Ramachander, J. U. Bowie, SAM domains can advance agnate surfaces for the accumulation of polymers and bankrupt oligomers. J. Mol. Biol. 342, 1353–1358 (2004). pmid:15364564
G. Xu, G. Jansen, D. Y. Thomas, C. P. Hollenberg, M. Ramezani Rad, Ste50p sustains alliance pheromone-induced arresting transduction in the aggrandize Saccharomyces cerevisiae. Mol. Microbiol. 20, 773–783 (1996). pmid:8793874
M. Ramezani-Rad, The role of adaptor protein Ste50-dependent adjustment of the MAPKKK Ste11 in assorted signalling pathways of yeast. Curr. Genet. 43, 161–170 (2003). pmid:12764668
J. J. Kwan, N. Warner, T. Pawson, L. W. Donaldson, The band-aid anatomy of the S. cerevisiae Ste11 MAPKKK SAM area and its affiliation with Ste50. J. Mol. Biol. 342, 681–693 (2004). pmid:15327964
S. J. Grimshaw, H. R. Mott, K. M. Stott, P. R. Nielsen, K. A. Evetts, L. J. Hopkins, D. Nietlispach, D. Owen, Anatomy of the antiseptic alpha burden (SAM) area of the Saccharomyces cerevisiae mitogen-activated protein kinase pathway-modulating protein STE50 and appraisal of its alternation with the STE11 SAM. J. Biol. Chem. 279, 2192–2201 (2004). pmid:14573615
K. Bruckner, R. Klein, Signaling by Eph receptors and their ephrin ligands. Curr. Opin. Neurobiol. 8, 375–382 (1998). pmid:9687349
M. Smalla, P. Schmieder, M. Kelly, A. Ter Laak, G. Krause, L. Ball, M. Wahl, P. Bork, H. Oschkinat, Band-aid anatomy of the receptor tyrosine kinase EphB2 SAM area and identification of two audible typic alternation sites. Protein Sci. 8, 1954–1961 (1999). pmid:10548040
C. D. Thanos, S. Faham, K. E. Goodwill, D. Cascio, M. Phillips, J. U. Bowie, Monomeric anatomy of the beastly EphB2 antiseptic alpha burden domain. J. Biol. Chem. 274, 37301–37306 (1999). pmid:10601296
C. D. Thanos, K. E. Goodwill, J. U. Bowie, Oligomeric anatomy of the beastly EphB2 receptor SAM domain. Science 283, 833–836 (1999). pmid:9933164
D. Stapleton, I. Balan, T. Pawson, F. Sicheri, The clear anatomy of an Eph receptor SAM area reveals a apparatus for modular dimerization. Nat. Struct. Biol. 6, 44–49 (1999). pmid:9886291
K. Kullander, N. K. Mather, F. Diella, M. Dottori, A. W. Boyd, R. Klein, Kinase-dependent and kinase-independent functions of EphA4 receptors in aloft axon amplitude accumulation in vivo. Neuron 29, 73–84 (2001). pmid:11182082
E. K. Park, N. Warner, Y. S. Bong, D. Stapleton, R. Maeda, T. Pawson, I. O. Daar, Ectopic EphA4 receptor induces after protrusions via FGF signaling in Xenopus embryos. Mol. Biol. Corpuscle 15, 1647–1655 (2004). pmid:14742708
M. Sheng, E. Kim, The brand ancestors of arch proteins. J. Corpuscle Sci. 113, 1851–1856 (2000). pmid:10806096
S. Naisbitt, E. Kim, J. C. Tu, B. Xiao, C. Sala, J. Valtschanoff, R. J. Weinberg, P. F. Worley, M. Sheng, Shank, a atypical ancestors of postsynaptic body proteins that binds to the NMDA receptor/PSD-95/GKAP circuitous and cortactin. Neuron 23, 569–582 (1999). pmid:10433268
H. Zhang, Q. Xu, S. Krajewski, M. Krajewska, Z. Xie, S. Fuess, S. Kitada, K. Pawlowski, A. Godzik, J. C. Reed, BAR: An apoptosis regulator at the circle of caspases and Bcl-2 ancestors proteins. Proc. Natl. Acad. Sci. U.S.A. 97, 2597–2602 (2000). pmid:10716992
S. Matsuda, J. C. Harries, M. Viskaduraki, P. J. Troke, K. B. Kindle, C. Ryan, D. M. Heery, A conserved alpha-helical burden mediates the bounden of assorted nuclear proteins to the SRC1 alternation area of CBP. J. Biol. Chem. 279, 14055–14064 (2004). pmid:14722092
T. L. Tootle, P. S. Lee, I. Rebay, CRM1-mediated nuclear consign and adapted action of the Receptor Tyrosine Kinase adversary YAN crave specific interactions with MAE. Development 130, 845–857 (2003). pmid:12538513
S. R. Chakrabarti, R. Sood, S. Ganguly, S. Bohlander, Z. Shen, G. Nucifora, Modulation of TEL archetype action by alternation with the ubiquitin-conjugating agitator UBC9. Proc. Natl. Acad. Sci. U.S.A. 96, 7467–7472 (1999). pmid:10377438
S. R. Chakrabarti, R. Sood, S. Nandi, G. Nucifora, Posttranslational modification of TEL and TEL/AML1 by SUMO-1 and cell-cycle-dependent accumulation into nuclear bodies. Proc. Natl. Acad. Sci. U.S.A. 97, 13281–13285 (2000). pmid:11078523
H. Zhang, G. A. Smolen, R. Palmer, A. Christoforou, S. van den Heuvel, D. A. Haber, SUMO modification is appropriate for in vivo Hox gene adjustment by the Caenorhabditis elegans Polycomb accumulation protein SOP-2. Nat. Genet. 36, 507–511 (2004). pmid:15107848
F. N. Barrera, J. A. Poveda, J. M. Gonzalez-Ros, J. L. Neira, Bounden of the C-terminal SAM area of beastly p73 to lipid membranes. J. Biol. Chem. 278, 46878–46885 (2003). pmid:12954612
We acknowledge M. J. Budny, M. Sawaya, B. Harada, and M. Plotkowski for accessible discussions and comments. The authors are accurate by NIH admission R01 CA081000. J.U.B. is a Leukemia and Lymphoma Society scholar.
8 Various Ways To Do Cbp Form 8 | Cbp Form 8 – cbp form 3078
| Encouraged for you to my website, within this time period I’ll explain to you regarding cbp form 3078