PTPN21 and Hook3 relieve KIF1C autoinhibition and activate intracellular transport

Nida Siddiqui; Alexander James Zwetsloot; Alice Bachmann; Daniel Roth; Hamdi Hussain; Jonathan Brandt; Irina Kaverina; Anne Straube

doi:10.1038/s41467-019-10644-9

PTPN21 and Hook3 relieve KIF1C autoinhibition and activate intracellular transport

Nat Commun. 2019 Jun 19;10(1):2693. doi: 10.1038/s41467-019-10644-9.

Authors

Nida Siddiqui^{1

2}, Alexander James Zwetsloot^{1

3}, Alice Bachmann^{1

2}, Daniel Roth^{1

2}, Hamdi Hussain^{1

2}, Jonathan Brandt^{1

2}, Irina Kaverina⁴, Anne Straube^{5

6}

Affiliations

¹ Centre for Mechanochemical Cell Biology, University of Warwick, Coventry, CV4 7AL, UK.
² Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
³ MRC-DTP in Interdisciplinary Biomedical Research, Warwick Medical School, Coventry, CV4 7AL, UK.
⁴ Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, 37232, TN, USA.
⁵ Centre for Mechanochemical Cell Biology, University of Warwick, Coventry, CV4 7AL, UK. anne@mechanochemistry.org.
⁶ Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK. anne@mechanochemistry.org.

Abstract

The kinesin-3 KIF1C is a fast organelle transporter implicated in the transport of dense core vesicles in neurons and the delivery of integrins to cell adhesions. Here we report the mechanisms of autoinhibition and release that control the activity of KIF1C. We show that the microtubule binding surface of KIF1C motor domain interacts with its stalk and that these autoinhibitory interactions are released upon binding of protein tyrosine phosphatase PTPN21. The FERM domain of PTPN21 stimulates dense core vesicle transport in primary hippocampal neurons and rescues integrin trafficking in KIF1C-depleted cells. In vitro, human full-length KIF1C is a processive, plus-end directed motor. Its landing rate onto microtubules increases in the presence of either PTPN21 FERM domain or the cargo adapter Hook3 that binds the same region of KIF1C tail. This autoinhibition release mechanism allows cargo-activated transport and might enable motors to participate in bidirectional cargo transport without undertaking a tug-of-war.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biological Transport
Cell Line
Cytoplasmic Vesicles / metabolism
Hippocampus / cytology
Humans
Integrins / metabolism
Intravital Microscopy / methods
Kinesins / genetics
Kinesins / isolation & purification
Kinesins / metabolism*
Mice
Microtubule-Associated Proteins / isolation & purification
Microtubule-Associated Proteins / metabolism*
Microtubules / metabolism
Neurons / cytology
Primary Cell Culture
Protein Binding
Protein Domains
Protein Tyrosine Phosphatases, Non-Receptor / genetics
Protein Tyrosine Phosphatases, Non-Receptor / isolation & purification
Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
RNA, Small Interfering / metabolism
Rats
Recombinant Proteins / genetics
Recombinant Proteins / isolation & purification
Recombinant Proteins / metabolism
Single Molecule Imaging / methods

Substances

Integrins
KIF1C protein, human
Kif1c protein, mouse
Microtubule-Associated Proteins
RNA, Small Interfering
Recombinant Proteins
hook3 protein, human
PTPN21 protein, human
Protein Tyrosine Phosphatases, Non-Receptor
Ptpn21 protein, mouse
Kinesins

Abstract

Publication types

MeSH terms

Substances

Grants and funding