期刊
SCIENCE ADVANCES
卷 7, 期 47, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abj9812
关键词
-
资金
- University of Michigan
- National Institutes of Health [GM094231, GM136822, GM121491, GM086610, K12 GM111725, S10OD020011]
KIFBP is found to remodel kinesin motors and block microtubule binding by inducing allosteric changes to kinesin and sterically blocking access to the microtubule. The study also identifies two regions of KIFBP essential for kinesin binding and cellular regulation during mitosis.
Kinesins are regulated in space and time to ensure activation only in the presence of cargo. Kinesin-binding protein (KIFBP), which is mutated in Goldberg-Shprintzen syndrome, binds to and inhibits the catalytic motor heads of 8 of 45 kinesin superfamily members, but the mechanism remains poorly defined. Here, we used cryo-electron microscopy and cross-linking mass spectrometry to determine high-resolution structures of KIFBP alone and in complex with two mitotic kinesins, revealing structural remodeling of kinesin by KIFBP. We find that KIFBP remodels kinesin motors and blocks microtubule binding (i) via allosteric changes to kinesin and (ii) by sterically blocking access to the microtubule. We identified two regions of KIFBP necessary for kinesin binding and cellular regulation during mitosis. Together, this work further elucidates the molecular mechanism of KIFBP-mediated kinesin inhibition and supports a model in which structural rearrangement of kinesin motor domains by KIFBP abrogates motor protein activity.
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