The SAM domain of polyhomeotic, RAE28, and Scm mediates specific interactions through conserved residues

Kyba, Michael; Brock, Hugh W.

doi:10.1002/(sici)1520-6408(1998)22:1<74::aid-dvg8>3.0.co;2-4

Cited by 63 publications

(11 citation statements)

References 39 publications

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“…Sfmbt is part of a PcG complex called Pho-RC, which is important for targeting PcG proteins to specific DNA sequences recognized by the Pho subunit [ 53 , 54 ]. SCM strongly interacts with PRC1 through SAM–SAM interactions between Ph and SCM [ 55 , 56 ], and it can also interact with PRC2 [ 57 ]. The SAM of SCM can co-polymerize with Ph [ 58 ], and can also interact with the SAM of Sfmbt, allowing a “tri-SAM” network to form (Ph–SCM–Sfmbt).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Polyhomeotic Condensates by Intrinsically Disordered Sequences That Affect Chromatin Binding

2022

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The Polycomb group (PcG) complex PRC1 localizes in the nucleus in condensed structures called Polycomb bodies. The PRC1 subunit Polyhomeotic (Ph) contains an oligomerizing sterile alpha motif (SAM) that is implicated in both PcG body formation and chromatin organization in Drosophila and mammalian cells. A truncated version of Ph containing the SAM (mini-Ph) forms phase-separated condensates with DNA or chromatin in vitro, suggesting that PcG bodies may form through SAM-driven phase separation. In cells, Ph forms multiple small condensates, while mini-Ph typically forms a single large nuclear condensate. We therefore hypothesized that sequences outside of mini-Ph, which are predicted to be intrinsically disordered, are required for proper condensate formation. We identified three distinct low-complexity regions in Ph based on sequence composition. We systematically tested the role of each of these sequences in Ph condensates using live imaging of transfected Drosophila S2 cells. Each sequence uniquely affected Ph SAM-dependent condensate size, number, and morphology, but the most dramatic effects occurred when the central, glutamine-rich intrinsically disordered region (IDR) was removed, which resulted in large Ph condensates. Like mini-Ph condensates, condensates lacking the glutamine-rich IDR excluded chromatin. Chromatin fractionation experiments indicated that the removal of the glutamine-rich IDR reduced chromatin binding and that the removal of either of the other IDRs increased chromatin binding. Our data suggest that all three IDRs, and functional interactions among them, regulate Ph condensate size and number. Our results can be explained by a model in which tight chromatin binding by Ph IDRs antagonizes Ph SAM-driven phase separation. Our observations highlight the complexity of regulation of biological condensates housed in single proteins.

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Section: Discussionmentioning

confidence: 99%

Regulation of Polyhomeotic Condensates by Intrinsically Disordered Sequences That Affect Chromatin Binding

2022

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“…SAM domains play a functional role in mediating the homotypic and heterotypic dimerization of the transcription factor TEL 14 , members of the Polycomb group of transcriptional repressors (RAE28, Scm, ph) 15,16 , protein kinase Byr2p 17 , and the α/β isoforms of the liprin scaffolding proteins 18 . Interestingly, translocations that create oncogenic forms of the βPDGF receptor 19 , c-Abl 20 , JAK2 21 and AML1 22 can result from chimeric fusions to the TEL SAM domain.…”

Section: Lettersmentioning

confidence: 99%

“…When mutations that map to conserved features of the subunit core -and therefore are likely to disrupt the subunit fold -are eliminated, two informative mutations are discernable. The homo-and hetero-typic dimerization of the Polycomb transcriptional repressors RAE28, ph, and Scm, is abolished by mutation of two residues predicted to map to the dimer interface 16 . These residues, Ile 62 and Trp 1 of the ph SAM domain, correspond closely to the N-terminal strand residue Phe 910 and the α5 helix residue Met 972, respectively, of the EphA4 SAM domain.…”

Section: Lettersmentioning

confidence: 99%

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et al. 1999

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The sterile alpha motif (SAM) domain is a novel protein module of approximately 70 amino acids that is found in a variety of signaling molecules including tyrosine and serine/threonine protein kinases, cytoplasmic scaffolding and adaptor proteins, regulators of lipid metabolism, and GTPases as well as members of the ETS family of transcription factors. The SAM domain can potentially function as a protein interaction module through the ability to homo- and hetero-oligomerize with other SAM domains. This functional property elicits the oncogenic activation of chimeric proteins arising from translocation of the SAM domain of TEL to coding regions of the betaPDGF receptor, Abl, JAK2 protein kinase and the AML1 transcription factor. Here we describe the 2.0 A X-ray crystal structure of a SAM domain homodimer from the intracellular region of the EphA4 receptor tyrosine kinase. The structure reveals a mode of dimerization that we predict is shared amongst the SAM domains of the Eph receptor tyrosine kinases and possibly other SAM domain containing proteins. These data indicate a mechanism through which an independently folding protein module can form homophilic complexes that regulate signaling events at the membrane and in the nucleus.

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“…SAM domains (also known as SPM, HLH or Pointed domains) have been found in >250 regulatory proteins including receptor tyrosine kinases, serine/threonine kinases, adapter proteins and transcription factors (Ponting, 1995; Schultz et al ., 1997; Kyba and Brock, 1998). Some SAM domains are known to form homotypic or heterotypic oligomers and could thereby serve to organize protein complexes in the cell (Carroll et al ., 1996; Golub et al ., 1996; Jousset et al ., 1997; Peterson et al ., 1997; Tu et al ., 1997; Kwiatkowski et al ., 1998; Poirel et al ., 2000; Potter et al ., 2000; Baker et al ., 2001).…”

Section: Introductionmentioning

confidence: 99%

Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression

2001

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TEL is a transcriptional repressor that is a frequent target of chromosomal translocations in a large number of hematalogical malignancies. These rearrangements fuse a potent oligomerization module, the SAM domain of TEL, to a variety of tyrosine kinases or transcriptional regulatory proteins. The self-associating property of TEL±SAM is essential for cell transformation in many, if not all of these diseases. Here we show that the TEL±SAM domain forms a helical, head-to-tail polymeric structure held together by strong intermolecular contacts, providing the ®rst clear demonstration that SAM domains can polymerize. Our results also suggest a mechanism by which SAM domains could mediate the spreading of transcriptional repression complexes along the chromosome.

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The SAM domain of polyhomeotic, RAE28, and Scm mediates specific interactions through conserved residues

Cited by 63 publications

References 39 publications

Regulation of Polyhomeotic Condensates by Intrinsically Disordered Sequences That Affect Chromatin Binding

Regulation of Polyhomeotic Condensates by Intrinsically Disordered Sequences That Affect Chromatin Binding

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Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression

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