The kinesin-1 motor protein is regulated by a direct interaction of its head and tail

Kristen A. Dietrich, Charles V. Sindelar, Paul D. Brewer, Kenneth H. Downing, Christine R. Cremo, Sarah E. Rice

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Kinesin-1 is a molecular motor protein that transports cargo along microtubules. Inside cells, the vast majority of kinesin-1 is regulated to conserve ATP and to ensure its proper intracellular distribution and coordination with other molecular motors. Regulated kinesin-1 folds in half at a hinge in its coiled-coil stalk. Interactions between coiled-coil regions near the enzymatically active heads at the N terminus and the regulatory tails at the C terminus bring these globular elements in proximity and stabilize the folded conformation. However, it has remained a mystery how kinesin-1's microtubule-stimulated ATPase activity is regulated in this folded conformation. Here, we present evidence for a direct interaction between the kinesin-1 head and tail. We photochemically cross-linked heads and tails and produced an 8-Å cryoEM reconstruction of the cross-linked head-tail complex on microtubules. These data demonstrate that a conserved essential regulatory element in the kinesin-1 tail interacts directly and specifically with the enzymatically critical Switch I region of the head. This interaction suggests a mechanism for tail-mediated regulation of the ATPase activity of kinesin-1. In our structure, the tail makes simultaneous contacts with the kinesin-1 head and the microtubule, suggesting the tail may both regulate kinesin-1 in solution and hold it in a paused state with high ADP affinity on microtubules. The interaction of the Switch I region of the kinesin-1 head with the tail is strikingly similar to the interactions of small GTPases with their regulators, indicating that other kinesin motors may share similar regulatory mechanisms.

Original languageEnglish (US)
Pages (from-to)8938-8943
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number26
DOIs
StatePublished - Jul 1 2008

Keywords

  • Cross-linking
  • Electron microscopy
  • Regulation
  • Switch

ASJC Scopus subject areas

  • General

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