6mlq
From Proteopedia
Cryo-EM structure of microtubule-bound Kif7 in the ADP state
Structural highlights
Disease[KIF7_HUMAN] Joubert syndrome;Hydrolethalus;Joubert syndrome with ocular defect;Joubert syndrome with orofaciodigital defect;Multiple epiphyseal dysplasia, Al-Gazali type;Acrocallosal syndrome. Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, and hydrolethalus syndrome among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome influence the clinical outcome. Primary ciliopathy loci can be modulated by pathogenic lesions in other ciliary genes to either exacerbate overall severity or induce specific endophenotypes. KIF7 may be causally associated with diverse ciliopathies, and also acts as a modifier gene across the ciliopathy spectrum. The gene represented in this entry may act as a disease modifier. Heterozygous missense mutations in KIF7 may genetically interact with other BBS genes and contribute to disease manifestation and severity. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry may be involved in disease pathogenesis. Function[TBA1A_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [KIF7_HUMAN] Acts as both a negative and positive regulator of sonic hedgehog (Shh) pathway, acting downstream of SMO. Negatively regulates the pathway by preventing inappropriate activation of the transcriptional activator GLI2 in the absence of ligand. Positively regulates the pathway by preventing the processing of the transcription factor GLI3 into its repressor form. Required for efficient localization of GLI3 to cilia in response to Shh. Affects microtubular dynamics and acts as a ciliary motor.[1] [TBB_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. Publication Abstract from PubMedThe correct localization of Hedgehog effectors to the tip of primary cilia is critical for proper signal transduction. The conserved non-motile kinesin Kif7 defines a "cilium-tip compartment" by localizing to the distal ends of axonemal microtubules. How Kif7 recognizes microtubule ends remains unknown. We find that Kif7 preferentially binds GTP-tubulin at microtubule ends over GDP-tubulin in the mature microtubule lattice, and ATP hydrolysis by Kif7 enhances this discrimination. Cryo-electron microscopy (cryo-EM) structures suggest that a rotated microtubule footprint and conformational changes in the ATP-binding pocket underlie Kif7's atypical microtubule-binding properties. Finally, Kif7 not only recognizes but also stabilizes a GTP-form of tubulin to promote its own microtubule-end localization. Thus, unlike the characteristic microtubule-regulated ATPase activity of kinesins, Kif7 modulates the tubulin mechanochemical cycle. We propose that the ubiquitous kinesin fold has been repurposed in Kif7 to facilitate organization of a spatially restricted platform for localization of Hedgehog effectors at the cilium tip. Interplay between the Kinesin and Tubulin Mechanochemical Cycles Underlies Microtubule Tip Tracking by the Non-motile Ciliary Kinesin Kif7.,Jiang S, Mani N, Wilson-Kubalek EM, Ku PI, Milligan RA, Subramanian R Dev Cell. 2019 Apr 19. pii: S1534-5807(19)30241-2. doi:, 10.1016/j.devcel.2019.04.001. PMID:31031197[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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