Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.77779
Keywords
cytokinesis; ESCRT; abscission checkpoint; protein structure; protein-protein interactions; Human
Categories
Funding
- National Cancer Institute of the National Institutes of Health [P30CA042014]
- NIH [5R01GM112080, 5R01GM131052, F31GM139318]
- American Cancer Society Postdoctoral Fellowship [PF-14-102-01-CMS]
- U.S. Department of Energy, Offices of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIH, National Institute of General Medicine Sciences [P41GM103393]
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In this study, the interactions between human MIT domains and ESCRT-III tails were comprehensively mapped and quantified. Several new interactions were discovered, and the structure of the SPASTIN MIT domain in complex with the IST1 C-terminal tail was reported. The study also revealed the localization and functions of three MIT enzymes in cytokinetic abscission.
The 12 related human ESCRT-III proteins form filaments that constrict membranes and mediate fission, including during cytokinetic abscission. The C-terminal tails of polymerized ESCRT-III subunits also bind proteins that contain Microtubule-Interacting and Trafficking (MIT) domains. MIT domains can interact with ESCRT-III tails in many different ways to create a complex binding code that is used to recruit essential cofactors to sites of ESCRT activity. Here, we have comprehensively and quantitatively mapped the interactions between all known ESCRT-III tails and 19 recombinant human MIT domains. We measured 228 pairwise interactions, quantified 60 positive interactions, and discovered 18 previously unreported interactions. We also report the crystal structure of the SPASTIN MIT domain in complex with the IST1 C-terminal tail. Three MIT enzymes were studied in detail and shown to: (1) localize to cytokinetic midbody membrane bridges through interactions with their specific ESCRT-III binding partners (SPASTIN-IST1, KATNA1-CHMP3, and CAPN7-IST1), (2) function in abscission (SPASTIN, KATNA1, and CAPN7), and (3) function in the 'NoCut' abscission checkpoint (SPASTIN and CAPN7). Our studies define the human MIT-ESCRT-III interactome, identify new factors and activities required for cytokinetic abscission and its regulation, and provide a platform for analyzing ESCRT-III and MIT cofactor interactions in all ESCRT-mediated processes.
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