Positive charge in the K-loop of the kinesin-3 motor KIF1A regulates superprocessivity by enhancing microtubule affinity in the one-head–bound state

Zaniewski, Taylor M.; Hancock, William O.

doi:10.1016/j.jbc.2022.102818

Cited by 8 publications

(23 citation statements)

References 57 publications

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“…These observations strongly indicate that KIF1A’s two motor domains move in a coordinated manner. However, our conclusion contrasts a recently proposed model in which KIF1A’s superprocessivity arises from a K-loop-dependent enhanced-MT affinity in the detachment-prone, single-head-bound state of the motor, rather than from a tight coordination between KIF1A’s two motor domains 75 . This model was based in part on the assumption that the neck-linker of KIF1A is longer than the one of kinesin-1 75, 84 .…”

Section: Discussioncontrasting

confidence: 99%

“…However, our conclusion contrasts a recently proposed model in which KIF1A’s superprocessivity arises from a K-loop-dependent enhanced-MT affinity in the detachment-prone, single-head-bound state of the motor, rather than from a tight coordination between KIF1A’s two motor domains 75 . This model was based in part on the assumption that the neck-linker of KIF1A is longer than the one of kinesin-1 75, 84 . However, our structures show that the KIF1A neck-linker is actually shorter than the neck-linker of kinesin-1 and other kinesins.…”

Section: Discussioncontrasting

confidence: 99%

“…These results show that the KIF1A K-loop and the less positively charged loop-12 of KIF14 are not functionally equivalent and that an intact K-loop is necessary for the characteristic long run length of KIF1A. This is consistent with a recent study showing that the KIF1A run length scales with the number of positively charged residues in the K-loop 75 . These results appear difficult to reconcile with the fact that most of the K-loop lysines in the structures of the KIF1A-MT complexes appear far from the MT surface or the rest of the kinesin motor domain (Fig.…”

Section: Resultssupporting

confidence: 90%

“…We show that replacing KIF1A’s K-loop for loop-12 of the kinesin-3 motor, KIF14, which has only a single positively charged residue located close to the MT interface, results in a significant reduction of the run-length of the motor. This result is consistent with recent reports that show that KIF1A’s K-loop and its positively-charged residues are essential for KIF1A’s superprocessivity 74, 75 .…”

Section: Discussionsupporting

confidence: 94%

“…KIF1A, like other kinesin-3 family members, has an elongated Lys-rich loop-12 referred to as the K-loop. While it has been shown that the K-loop is important for KIF1A-MT binding [72][73][74][75] , how it interacts with MTs has not been clear as most of this loop is either disordered or not resolved in X-ray crystal structures of KIF1A and in lower resolution cryo-EM structures of KIF1A-MT complexes. Our high-resolution structures of KIF1A-MT complexes show the complete polypeptide path of the K-loop (Fig.…”

Section: Structure and Role Of The Kif1a-sepcific K-loopmentioning

confidence: 99%

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Cryo-EM Unveils the Processivity Mechanism of Kinesin KIF1A and the Impact of its Pathogenic Variant P305L

Benoit

Rao

Asenjo

et al. 2023

Preprint

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Mutations in the Kinesin-3 motor KIF1A, a microtubule (MT)-associated motor protein, cause devastating neurodevelopmental and neurodegenerative diseases termed KIF1A-associated neurological disorders (KAND). While the mechanism of KIF1A is increasingly understood, high resolution (<4 Å) structural information of KIF1A-MT complexes is lacking. Here, we present 2.7-3.4 Å resolution structures of dimeric MT-bound wild-type (WT) KIF1A and the pathogenic P305L mutant as a function of the nucleotide state. Our structures reveal that 1) the KIF1A dimer binds MTs in one- and two-heads-bound states, 2) that both MT-bound heads assume distinct conformations with tight inter-head connection, 3) the position and conformation of the class-specific loop 12 (the K-loop), and 4) that the P305L mutation causes structural changes in the K-loop that result in a weakly MT-bound state. Motivated by our structural insights, we performed structure-function studies that reveal that both the K-loop and head-head coordination are major determinants of KIF1A's superprocessive motility. Our work provides key insights into the mechanism of KIF1A and provides near-atomic structures of WT and mutant KIF1A for future structure-guided drug-design approaches to treat KAND.

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Section: Discussioncontrasting

confidence: 99%