7EOB

Crystal structure of KIF1A Motor-Neck domain E239K mutant with ADP-Mg-AlFx

Summary for 7EOB

• Entry DOI: 10.2210/pdb7eob/pdb
• Descriptor: Kinesin-like protein KIF1A, ALUMINUM FLUORIDE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kinesin, motor protein
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 1
• Total formula weight: 44508.03

Authors

Ogawa, T.,Jiang, X.,Hirokawa, N. (deposition date: 2021-04-21, release date: 2021-12-29, Last modification date: 2023-11-29)

Primary citation

Morikawa, M.,Jerath, N.U.,Ogawa, T.,Morikawa, M.,Tanaka, Y.,Shy, M.E.,Zuchner, S.,Hirokawa, N.
A neuropathy-associated kinesin KIF1A mutation hyper-stabilizes the motor-neck interaction during the ATPase cycle.
Embo J., 41:e108899-e108899, 2022

PubMed Abstract: The mechanochemical coupling of ATPase hydrolysis and conformational dynamics in kinesin motors facilitates intramolecular interaction cycles between the kinesin motor and neck domains, which are essential for microtubule-based motility. Here, we characterized a charge-inverting KIF1A-E239K mutant that we identified in a family with axonal-type Charcot-Marie-Tooth disease and also in 24 cases in human neuropathies including spastic paraplegia and hereditary sensory and autonomic neuropathy. We show that Glu239 in the β7 strand is a key residue of the motor domain that regulates the motor-neck interaction. Expression of the KIF1A-E239K mutation has decreased ability to complement Kif1a neurons, and significantly decreases ATPase activity and microtubule gliding velocity. X-ray crystallography shows that this mutation causes an excess positive charge on β7, which may electrostatically interact with a negative charge on the neck. Quantitative mass spectrometric analysis supports that the mutation hyper-stabilizes the motor-neck interaction at the late ATP hydrolysis stage. Thus, the negative charge of Glu239 dynamically regulates the kinesin motor-neck interaction, promoting release of the neck from the motor domain upon ATP hydrolysis.

PubMed: 35132656
DOI: 10.15252/embj.2021108899

Experimental method

X-RAY DIFFRACTION (1.76 Å)