Autoinhibited kinesin-1 adopts a hierarchical folding pattern

Author:

Tan Zhenyu12ORCID,Yue Yang3,Leprevost Felipe4,Haynes Sarah4,Basrur Venkatesha4,Nesvizhskii Alexey I45,Verhey Kristen J3ORCID,Cianfrocco Michael A26ORCID

Affiliation:

1. Department of Biophysics, University of Michigan

2. Life Sciences Institute, University of Michigan

3. Department of Cell & Developmental Biology, University of Michigan

4. Department of Pathology, University of Michigan

5. Department of Computational Medicine and Bioinformatics, University of Michigan

6. Department of Biological Chemistry, University of Michigan

Abstract

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.

Funder

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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