Structural and functional insight into regulation o kinesin-1 by microtubule-associated protein MAP7

Luke S. Ferro; Qianglin Fang; Lisa Eshun-Wilson; Jonathan Fernandes; Amanda Jack; Daniel P. Farrell; Mert Golcuk; Teun Huijben; Katelyn Costa; Mert Gur; Frank DiMaio; Eva Nogales; Ahmet Yildiz

doi:10.1126/science.abf6154

Structural and functional insight into regulation o kinesin-1 by microtubule-associated protein MAP7

Luke S. Ferro, Qianglin Fang^*, Lisa Eshun-Wilson, Jonathan Fernandes, Amanda Jack, Daniel P. Farrell, Mert Golcuk, Teun Huijben, Katelyn Costa, Mert Gur, Frank DiMaio, Eva Nogales^*, Ahmet Yildiz^*

^*Corresponding author for this work

Department of Mechanical Engineering

Research output: Contribution to journal › Article › peer-review

49 Citations (Scopus)

Abstract

Microtubule (MT)-associated protein 7 (MAP7) is a required cofactor for kinesin-1-driven transport of intracellular cargoes. Using cryo-electron microscopy and single-molecule imaging, we investigated how MAP7 binds MTs and facilitates kinesin-1 motility. The MT-binding domain (MTBD) of MAP7 bound MTs as an extended a helix between the protofilament ridge and the site of lateral contact. Unexpectedly, the MTBD partially overlapped with the binding site of kinesin-1 and inhibited its motility. However, by tethering kinesin-1 to the MT, the projection domain of MAP7 prevented dissociation of the motor and facilitated its binding to available neighboring sites. The inhibitory effect of the MTBD dominated as MTs became saturated with MAP7. Our results reveal biphasic regulation of kinesin-1 by MAP7 in the context of their competitive binding to MTs.

Original language	English
Article number	eabf6154
Journal	Science
Volume	375
Issue number	6578
DOIs	https://doi.org/10.1126/science.abf6154
Publication status	Published - 21 Jan 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Funding

This work was supported by grants from the National Institute of General Medical Sciences (GM094522 (A.Y.), GM123655-03 (L.F.), GM051487 (E.N.), GM127018 (E.N.), and the National Science Foundation (MCB-1617028 and MCB-1055017, A.Y.), PRACE (2019215144, MG), and Istanbul Technical University BAP (MGA-2021-42803, MG). E.N. is a Howard Hughes Medical Institute Investigator.

Funders	Funder number
National Science Foundation	MCB-1617028, MCB-1055017
National Institute of General Medical Sciences	GM051487, R01GM123089, GM094522, GM123655-03, GM127018
Partnership for Advanced Computing in Europe AISBL	2019215144
Istanbul Teknik Üniversitesi	MGA-2021-42803

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title = "Structural and functional insight into regulation o kinesin-1 by microtubule-associated protein MAP7",

abstract = "Microtubule (MT)-associated protein 7 (MAP7) is a required cofactor for kinesin-1-driven transport of intracellular cargoes. Using cryo-electron microscopy and single-molecule imaging, we investigated how MAP7 binds MTs and facilitates kinesin-1 motility. The MT-binding domain (MTBD) of MAP7 bound MTs as an extended a helix between the protofilament ridge and the site of lateral contact. Unexpectedly, the MTBD partially overlapped with the binding site of kinesin-1 and inhibited its motility. However, by tethering kinesin-1 to the MT, the projection domain of MAP7 prevented dissociation of the motor and facilitated its binding to available neighboring sites. The inhibitory effect of the MTBD dominated as MTs became saturated with MAP7. Our results reveal biphasic regulation of kinesin-1 by MAP7 in the context of their competitive binding to MTs.",

author = "Ferro, {Luke S.} and Qianglin Fang and Lisa Eshun-Wilson and Jonathan Fernandes and Amanda Jack and Farrell, {Daniel P.} and Mert Golcuk and Teun Huijben and Katelyn Costa and Mert Gur and Frank DiMaio and Eva Nogales and Ahmet Yildiz",

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doi = "10.1126/science.abf6154",

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AU - Ferro, Luke S.

AU - Fang, Qianglin

AU - Eshun-Wilson, Lisa

AU - Fernandes, Jonathan

AU - Jack, Amanda

AU - Farrell, Daniel P.

AU - Golcuk, Mert

AU - Huijben, Teun

AU - Costa, Katelyn

AU - Gur, Mert

AU - DiMaio, Frank

AU - Nogales, Eva

AU - Yildiz, Ahmet

PY - 2022/1/21

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N2 - Microtubule (MT)-associated protein 7 (MAP7) is a required cofactor for kinesin-1-driven transport of intracellular cargoes. Using cryo-electron microscopy and single-molecule imaging, we investigated how MAP7 binds MTs and facilitates kinesin-1 motility. The MT-binding domain (MTBD) of MAP7 bound MTs as an extended a helix between the protofilament ridge and the site of lateral contact. Unexpectedly, the MTBD partially overlapped with the binding site of kinesin-1 and inhibited its motility. However, by tethering kinesin-1 to the MT, the projection domain of MAP7 prevented dissociation of the motor and facilitated its binding to available neighboring sites. The inhibitory effect of the MTBD dominated as MTs became saturated with MAP7. Our results reveal biphasic regulation of kinesin-1 by MAP7 in the context of their competitive binding to MTs.

AB - Microtubule (MT)-associated protein 7 (MAP7) is a required cofactor for kinesin-1-driven transport of intracellular cargoes. Using cryo-electron microscopy and single-molecule imaging, we investigated how MAP7 binds MTs and facilitates kinesin-1 motility. The MT-binding domain (MTBD) of MAP7 bound MTs as an extended a helix between the protofilament ridge and the site of lateral contact. Unexpectedly, the MTBD partially overlapped with the binding site of kinesin-1 and inhibited its motility. However, by tethering kinesin-1 to the MT, the projection domain of MAP7 prevented dissociation of the motor and facilitated its binding to available neighboring sites. The inhibitory effect of the MTBD dominated as MTs became saturated with MAP7. Our results reveal biphasic regulation of kinesin-1 by MAP7 in the context of their competitive binding to MTs.

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Structural and functional insight into regulation o kinesin-1 by microtubule-associated protein MAP7

Abstract

Bibliographical note

Funding

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