Motility and microtubule depolymerization mechanisms of the Kinesin-8 motor, KIF19A.
The kinesin-8 motor, KIF19A, accumulates at cilia tips and controls cilium length. Defective KIF19A leads to hydrocephalus and female infertility because of abnormally elongated cilia. Uniquely among kinesins, KIF19A possesses the dual functions of motility along ciliary microtubules and depolymerization of microtubules. To elucidate the molecular mechanisms of these functions we solved the crystal structure of its motor domain and determined its cryo-electron microscopy structure complexed with a microtubule. The features of KIF19A that enable its dual function are clustered on its microtubule-binding side. Unexpectedly, a destabilized switch II coordinates with a destabilized L8 to enable KIF19A to adjust to both straight and curved microtubule protofilaments. The basic clusters of L2 and L12 tether the microtubule. The long L2 with a characteristic acidic-hydrophobic-basic sequence effectively stabilizes the curved conformation of microtubule ends. Hence, KIF19A utilizes multiple strategies to accomplish the dual functions of motility and microtubule depolymerization by ATP hydrolysis.
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Molecular Structure and Dynamics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Doudou
D
Wang
RIKEN Center for Life Science Technologies, Yokohama, Japan.
Ryo
http://orcid.org/0000-0002-6537-9272
R
Nitta
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Molecular Structure and Dynamics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Manatsu
M
Morikawa
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Molecular Structure and Dynamics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Hiroaki
H
Yajima
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Molecular Structure and Dynamics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Shigeyuki
S
Inoue
RIKEN Center for Life Science Technologies, Yokohama, Japan.
Hideki
H
Shigematsu
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Masahide
M
Kikkawa
Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Molecular Structure and Dynamics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia.
Nobutaka
http://orcid.org/0000-0002-0081-5264
N
Hirokawa
X-ray crystallography; biophysics; cell biology; cryo-electron microscopy; kinesin; microtubule dynamic; mouse; structural biology
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