Autoinhibited kinesin-1 adopts a hierarchical folding pattern.

Autor:	Tan Z; Department of Biophysics, University of Michigan, Ann Arbor, United States.; Life Sciences Institute, University of Michigan, Ann Arbor, United States., Yue Y; Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, United States., Leprevost F; Department of Pathology, University of Michigan, Ann Arbor, United States., Haynes S; Department of Pathology, University of Michigan, Ann Arbor, United States., Basrur V; Department of Pathology, University of Michigan, Ann Arbor, United States., Nesvizhskii AI; Department of Pathology, University of Michigan, Ann Arbor, United States.; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, United States., Verhey KJ; Department of Cell & Developmental Biology, University of Michigan, Ann Arbor, United States., Cianfrocco MA; Life Sciences Institute, University of Michigan, Ann Arbor, United States.; Department of Biological Chemistry, University of Michigan, Ann Arbor, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2023 Nov 01; Vol. 12. Date of Electronic Publication: 2023 Nov 01.
DOI:	10.7554/eLife.86776
Abstrakt:	Conventional kinesin-1 is the primary anterograde motor in cells for transporting cellular cargo. While there is a consensus that the C-terminal tail of kinesin-1 inhibits motility, the molecular architecture of a full-length autoinhibited kinesin-1 remains unknown. Here, we combine crosslinking mass spectrometry (XL-MS), electron microscopy (EM), and AlphaFold structure prediction to determine the architecture of the full-length autoinhibited kinesin-1 homodimer (kinesin-1 heavy chain [KHC]) and kinesin-1 heterotetramer (KHC bound to kinesin light chain 1 [KLC1]). Our integrative analysis shows that kinesin-1 forms a compact, bent conformation through a break in coiled-coil 3. Moreover, our XL-MS analysis demonstrates that kinesin light chains stabilize the folded inhibited state rather than inducing a new structural state. Using our structural model, we show that disruption of multiple interactions between the motor, stalk, and tail domains is required to activate the full-length kinesin-1. Our work offers a conceptual framework for understanding how cargo adaptors and microtubule-associated proteins relieve autoinhibition to promote activation. Competing Interests: ZT, YY, FL, SH, VB, AN, KV, MC No competing interests declared (© 2023, Tan et al.)
Databáze:	MEDLINE
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