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PreprintCited by 29Microtubule and mitosis dynamicsGenetic and Kidney Cyst DiseasesBiotin and Related Studies

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KIF1C activates and extends dynein movement through the FHF cargo adaptor

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Ali, Ferdos Abid, Zwetsloot, Alexander J., Stone, Caroline E., Morgan, Tomos E., Wademan, Richard F., Carter, Andrew P., Straube, Anne·2023·Nature Structural & Molecular Biology
DOI 10.1101/2023.10.26.564242PMC PMC11996680

Preprint — published as 10.1038/s41594-024-01418-z · Paper page

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Abstract

Cellular cargos move bidirectionally on microtubules due to the presence of opposite polarity motors dynein and kinesin. Many studies show these motors are co-dependent, whereby one requires the activity of the other, although the mechanism is unknown. Here, using in vitro motility assays, we show that the kinesin-3 KIF1C acts both as an activator and a processivity factor for dynein. Activation only requires a fragment of the non-motor tail of KIF1C (KIF1C-stalk) to bind the cargo adaptor HOOK3. Cryo-EM, crosslinking mass spectrometry and AlphaFold2 predictions reveal this binding site to be separate from that of two constitutive factors (FTS and FHIP), which link HOOK3 to small G-proteins on cargos. We provide a structural model for how the FTS-HOOK3-FHIP1B (FHF) complex is auto-inhibited and explain how the KIF1C-stalk relieves this inhibition. Collectively, our work provides a molecular explanation for co-dependency by revealing that the mutual activation of dynein and kinesin is mediated through their shared adaptor. Many adaptors bind both dynein and kinesins, suggesting this mechanism could be generalised to other bidirectional complexes.

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Metadata

Authors
Ali, F. A., Zwetsloot, A. J., Stone, C. E., Morgan, T. E., Wademan, R. F., Carter, A. P., & Straube, A.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • University of Warwick (GB)
  • John Innes Centre (GB)
Corresponding author
  • Carter, Andrew P.
  • Straube, Anne
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
openRxiv
Published
2023-10-26
Volume
32
Issue
4
Pages
756-766
ISSN
1545-9985 (ISSN-L)
DOI
10.1101/2023.10.26.564242
PMC
PMC11996680
OpenAlex
W4405996020
Cited by
29
References
1
Citations by year
2026: 10 · 2025: 16 · 2024: 3
FWCI
12.98
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Structural & Molecular Biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
  • Explore Bristol Research (submittedVersion, cc-by)
  • Bristol Research (University of Bristol) (submittedVersion, cc-by)
Funders
  • Wellcome Trust
  • University of Warwick
  • Federal Aviation Administration
  • Medical Research Council (1788496, MC_UP_A025_1011, MR/N014294, MR/N014294/1)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Biotin and Related Studies
Keywords
KIF1C, kinesin-3, dynein, HOOK3, FTS, motor activation, autoinhibition
MeSH terms
Dyneins, Humans, Microtubule-Associated Proteins, Models, Molecular, Protein Binding, Kinesins, Intracellular Signaling Peptides and Proteins

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