| Structural highlights
9yai is a 6 chain structure with sequence from Homo sapiens and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 3.12Å |
| Ligands: | ANP, GDP, GTP, MG, TA1 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
KIF1A_HUMAN Autosomal dominant nonsyndromic intellectual disability;Hereditary sensory and autonomic neuropathy type 2;Autosomal recessive spastic paraplegia type 30. The disease is caused by mutations affecting the gene represented in this entry.[1] The disease is caused by mutations affecting the gene represented in this entry.[2] The disease is caused by mutations affecting the gene represented in this entry.[3]
Function
KIF1A_HUMAN Motor for anterograde axonal transport of synaptic vesicle precursors (By similarity).
Publication Abstract from PubMed
Pathogenic variants in the motor domain of the kinesin-3 motor protein KIF1A cause a range of neurodevelopmental and neurodegenerative conditions collectively termed KIF1A-associated neurological disorder (KAND). Among these, mutations at residue R350 are linked to hereditary spastic paraplegia and altered motor function. Yet, the structural basis for their pathogenicity remains unclear. Here, we present high-resolution cryo-electron microscopy (cryo-EM) structures of KIF1A R350G and R350W bound to microtubules in both the apo and AMP-PNP-bound states. We identify a salt bridge between KIF1A residue R350 and alpha-tubulin E415 that forms only in the open conformation of the motor domain and is disrupted in both mutants. The loss of this electrostatic interaction correlates with increased velocity, reduced processivity, and decreased microtubule affinity in the open, apo conformation, as demonstrated by single-molecule assays. Our results reveal an electrostatic interaction at the motor-microtubule interface that regulates KIF1A's motility behavior.
Pathogenic KIF1A R350 mutations disrupt a conserved and conformation-dependent kinesin-tubulin salt bridge.,Shatarupa A, Rao L, Asenjo AB, Gennerich A, Sosa H Nat Commun. 2026 Mar 31. doi: 10.1038/s41467-026-71026-6. PMID:41912506[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Erlich Y, Edvardson S, Hodges E, Zenvirt S, Thekkat P, Shaag A, Dor T, Hannon GJ, Elpeleg O. Exome sequencing and disease-network analysis of a single family implicate a mutation in KIF1A in hereditary spastic paraparesis. Genome Res. 2011 May;21(5):658-64. doi: 10.1101/gr.117143.110. Epub 2011 Apr 12. PMID:21487076 doi:https://dx.doi.org/10.1101/gr.117143.110
- ↑ Riviere JB, Ramalingam S, Lavastre V, Shekarabi M, Holbert S, Lafontaine J, Srour M, Merner N, Rochefort D, Hince P, Gaudet R, Mes-Masson AM, Baets J, Houlden H, Brais B, Nicholson GA, Van Esch H, Nafissi S, De Jonghe P, Reilly MM, Timmerman V, Dion PA, Rouleau GA. KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. Am J Hum Genet. 2011 Aug 12;89(2):219-30. doi: 10.1016/j.ajhg.2011.06.013. Epub, 2011 Aug 4. PMID:21820098 doi:https://dx.doi.org/10.1016/j.ajhg.2011.06.013
- ↑ Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D'Anjou G, Vanasse M, Srour M, Lafreniere RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011 Mar 11;88(3):306-16. doi: 10.1016/j.ajhg.2011.02.001. Epub, 2011 Mar 3. PMID:21376300 doi:10.1016/j.ajhg.2011.02.001
- ↑ Shatarupa A, Rao L, Asenjo AB, Gennerich A, Sosa H. Pathogenic KIF1A R350 mutations disrupt a conserved and conformation-dependent kinesin-tubulin salt bridge. Nat Commun. 2026 Mar 31;17(1):5175. doi: 10.1038/s41467-026-71026-6. PMID:41912506 doi:https://dx.doi.org/10.1038/s41467-026-71026-6
|
