PDF(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.
摘要：
微管相关运动蛋白KIF1A的突变导致严重的神经系统疾病，称为KIF1A相关神经系统疾病（KAND）。尽管深入了解其分子机制，KIF1A-微管复合物的高分辨率结构仍未定义。这里,我们展示了二聚体微管结合的KIF1A的2.7-3.5µ分辨率结构，包括致病性P305L突变体，跨越各种核苷酸状态。我们的结构显示KIF1A以单和双头结合的构型结合微管，两个头都表现出明显的构象，头间连接紧密。值得注意的是,KIF1A的类特异性环12（K环）与α-和β-微管蛋白的C末端尾巴形成静电相互作用。P305L突变不会破坏这些相互作用，但会改变loop-12的构象，损害强微管结合。结构功能分析揭示了K环和头-头协调是KIF1A超常运动的主要决定因素。我们的发现促进了对KIF1A分子机制的理解，并为开发针对KAND的结构指导疗法提供了基础。
