A highly conserved 310 helix within the kinesin motor domain is critical for kinesin function and human health

• Published in: Science advances 2021-04, Vol.7 (18)
• Main Authors: Lam, Aileen J, Rao, Lu, Anazawa, Yuzu, Okada, Kyoko, Chiba, Kyoko, Dacy, Mariah, Niwa, Shinsuke, Gennerich, Arne, Nowakowski, Dan W, McKenney, Richard J
• Format: Article
• Language: English
• Subjects: Biophysics; Health and Medicine; SciAdv r-articles
• ISSN: 2375-2548
• DOI: 10.1126/sciadv.abf1002

An uncharacterized structural element in the kinesin motor domain is shown to be critical for motor function and human health. KIF1A is a critical cargo transport motor within neurons. More than 100 known mutations result in KIF1A -associated neurological disorder (KAND), a degenerative condition for which there is no cure. A missense mutation, P305L, was identified in children diagnosed with KAND, but the molecular basis for the disease is unknown. We find that this conserved residue is part of an unusual 3 10 helix immediately adjacent to the family-specific K-loop, which facilitates a high microtubule-association rate. We find that the mutation negatively affects several biophysical parameters of the motor. However, the microtubule-association rate of the motor is most markedly affected, revealing that the presence of an intact K-loop is not sufficient for its function. We hypothesize that the 3 10 helix facilitates a specific K-loop conformation that is critical for its function. We find that the function of this proline is conserved in kinesin-1, revealing a fundamental principle of the kinesin motor mechanism.