title: Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations.
abstract: Tight regulation of kinesin activity is crucial and malfunction is linked to neurological diseases. Point mutations in the KIF21A gene cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by disrupting the autoinhibitory interaction between the motor domain and a regulatory region in the stalk. However, the molecular mechanism underlying the misregulation of KIF21A activity in CFEOM1 is not understood. Here, we show that the KIF21A regulatory domain containing all disease-associated substitutions in the stalk forms an intramolecular antiparallel coiled coil that inhibits the kinesin. CFEOM1 mutations lead to KIF21A hyperactivation by affecting either the structural integrity of the antiparallel coiled coil or the autoinhibitory binding interface, thereby reducing its affinity for the motor domain. Interaction of the KIF21A regulatory domain with the KIF21B motor domain and sequence similarities to KIF7 and KIF27 strongly suggest a conservation of this regulatory mechanism in other kinesin-4 family members.
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bianchi
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH, Utrecht, The Netherlands.
authors.forename: Wilhelmina E
authors.initials: WE
authors.lastname: van Riel
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Sebastian H W
authors.initials: SH
authors.lastname: Kraatz
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Natacha
authors.initials: N
authors.lastname: Olieric
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Frey
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH, Utrecht, The Netherlands.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Katrukha
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jaussi
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: John
authors.initials: J
authors.lastname: Missimer
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH, Utrecht, The Netherlands.
authors.forename: Ilya
authors.initials: I
authors.lastname: Grigoriev
authors.affiliation: Swiss Light Source, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Olieric
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Benoit
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH, Utrecht, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Akhmanova
authors.affiliation: Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kammerer
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005355:Fibrosis / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D062105:Molecular Docking Simulation; D009154:Mutation / Q000235:genetics; D015835:Ocular Motility Disorders / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D000072417:Protein Domains / Q000235:genetics*; D017510:Protein Folding
chemical_list: C119023:KIF21A protein, human; D016547:Kinesins