8UTV

KIF1A[1-393] P305L mutant ADP bound in complex with a microtubule

Summary for 8UTV

• Entry DOI: 10.2210/pdb8utv/pdb
• EMDB information: 42551
• Descriptor: Tubulin alpha-1B chain, Tubulin beta-2B chain, Kinesin-like protein KIF1A, ... (8 entities in total)
• Functional Keywords: kif1a, kinesin, motility, microtubule, tubulin, motor protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 202532.53

Authors

Benoit, M.P.M.H.,Rao, L.,Asenjo, A.B.,Gennerich, A.,Sosa, H. (deposition date: 2023-10-31, release date: 2024-06-12, Last modification date: 2024-07-31)

Primary citation

Benoit, M.P.M.H.,Rao, L.,Asenjo, A.B.,Gennerich, A.,Sosa, H.
Cryo-EM unveils kinesin KIF1A's processivity mechanism and the impact of its pathogenic variant P305L.
Nat Commun, 15:5530-5530, 2024

PubMed Abstract: Mutations in the microtubule-associated motor protein KIF1A lead to severe neurological conditions known as KIF1A-associated neurological disorders (KAND). Despite insights into its molecular mechanism, high-resolution structures of KIF1A-microtubule complexes remain undefined. Here, we present 2.7-3.5 Å resolution structures of dimeric microtubule-bound KIF1A, including the pathogenic P305L mutant, across various nucleotide states. Our structures reveal that KIF1A binds microtubules in one- and two-heads-bound configurations, with both heads exhibiting distinct conformations with tight inter-head connection. Notably, KIF1A's class-specific loop 12 (K-loop) forms electrostatic interactions with the C-terminal tails of both α- and β-tubulin. The P305L mutation does not disrupt these interactions but alters loop-12's conformation, impairing strong microtubule-binding. Structure-function analysis reveals the K-loop and head-head coordination as major determinants of KIF1A's superprocessive motility. Our findings advance the understanding of KIF1A's molecular mechanism and provide a basis for developing structure-guided therapeutics against KAND.

PubMed: 38956021
DOI: 10.1038/s41467-024-48720-4

Experimental method

ELECTRON MICROSCOPY (3 Å)