5wa1
CHMP4C A232T in complex with ALIX BRO1
Structural highlights
FunctionPDC6I_HUMAN Class E VPS protein involved in concentration and sorting of cargo proteins of the multivesicular body (MVB) for incorporation into intralumenal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome. Binds to the phospholipid lysobisphosphatidic acid (LBPA) which is abundant in MVBs internal membranes. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and enveloped virus budding (HIV-1 and other lentiviruses). Appears to be an adapter for a subset of ESCRT-III proteins, such as CHMP4, to function at distinct membranes. Required for completion of cytokinesis. Involved in HIV-1 virus budding. Can replace TSG101 it its role of supporting HIV-1 release; this function implies the interaction with CHMP4B. May play a role in the regulation of both apoptosis and cell proliferation.[1] [2] [3] [4] [5] [6] Publication Abstract from PubMedCytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4C (rs35094336, CHMP4C(T232)) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4C(T232) allele unwinds the C-terminal helix of CHMP4C, impairs binding to the early-acting ESCRT factor ALIX, and disrupts the abscission checkpoint. Cells expressing CHMP4C(T232) exhibit increased levels of DNA damage and are sensitized to several conditions that increase chromosome missegregation, including DNA replication stress, inhibition of the mitotic checkpoint, and loss of p53. Our data demonstrate the biological importance of the abscission checkpoint and suggest that dysregulation of abscission by CHMP4C(T232) may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis. A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability.,Sadler JBA, Wenzel DM, Williams LK, Guindo-Martinez M, Alam SL, Mercader JM, Torrents D, Ullman KS, Sundquist WI, Martin-Serrano J Proc Natl Acad Sci U S A. 2018 Sep 4. pii: 1805504115. doi:, 10.1073/pnas.1805504115. PMID:30181294[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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