5WA1

CHMP4C A232T in complex with ALIX BRO1

Summary for 5WA1

• Entry DOI: 10.2210/pdb5wa1/pdb
• Related: 3C3R
• Descriptor: Programmed cell death 6-interacting protein, Charged multivesicular body protein 4c (3 entities in total)
• Functional Keywords: cell division, transport protein, abscission checkpoint, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 44757.88

Authors

Wenzel, D.M.,Alam, S.L.,Sundquist, W.I. (deposition date: 2017-06-24, release date: 2018-09-19, Last modification date: 2023-10-04)

Primary citation

Sadler, J.B.A.,Wenzel, D.M.,Williams, L.K.,Guindo-Martinez, M.,Alam, S.L.,Mercader, J.M.,Torrents, D.,Ullman, K.S.,Sundquist, W.I.,Martin-Serrano, J.
A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability.
Proc. Natl. Acad. Sci. U.S.A., 115:E8900-E8908, 2018

PubMed Abstract: Cytokinetic 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) increases cancer susceptibility. Here, we explain the structural and functional basis for this cancer association: The CHMP4C 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 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 may synergize with oncogene-induced mitotic stress to promote genomic instability and tumorigenesis.

PubMed: 30181294
DOI: 10.1073/pnas.1805504115

Experimental method

X-RAY DIFFRACTION (1.868 Å)