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How the non-motile kinesin KIF7 adapts conserved kinesin principles for its function in Hedgehog signaling.

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Title: How the non-motile kinesin KIF7 adapts conserved kinesin principles for its function in Hedgehog signaling.
Authors: Haque F; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA., Srinivasu BY; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA., Engen JR; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA., Wales TE; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA., Subramanian R; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Source: BioRxiv : the preprint server for biology [bioRxiv] 2026 Feb 10. Date of Electronic Publication: 2026 Feb 10.
Publication Type: Journal Article; Preprint
Language: English
Journal Info: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Abstract: KIF7 is an atypical, non-motile kinesin that regulates Hedgehog signaling by concentrating GLI transcription factors at the cilium tip. How canonical kinesin principles for intracellular transport are repurposed to support KIF7's function as a signaling scaffold remains unclear. KIF7 exists in an autoinhibited state that is relieved by GLI binding, promoting microtubule association. We examined this regulatory mechanism by combining HDX-MS and AlphaFold modeling of a minimal KIF7 dimer, both alone and in complex with the GLI2 zinc-finger domain. Our HDX-MS data indicate that the highly negatively charged neck-coil dimerization domain of KIF7, which serves as the GLI2-binding site, is intramolecularly protected in the absence of GLI2. Consistent with this, AlphaFold models suggest that the motor domain folds back onto the neck-coil via KIF7's unusually long neck-linker, sterically occluding the microtubule-binding interface. This occurs through a mechanism conceptually analogous to, but structurally distinct from, autoinhibition in motile kinesins. GLI2 binding to the KIF7 neck-coil displaces the motor domain and induces allosteric changes that propagate to the microtubule-binding surface, thereby activating microtubule binding. ATP turnover further modulates KIF7's microtubule binding-unbinding equilibrium. Together, these findings reveal how a kinesin is adapted for a non-motile function as a scaffold in Hedgehog signaling.
References: J Cell Biol. 2018 Apr 2;217(4):1319-1334. (PMID: 29351996)
Commun Biol. 2025 Apr 29;8(1):679. (PMID: 40301632)
Curr Biol. 2009 Aug 11;19(15):1320-6. (PMID: 19592253)
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13377-82. (PMID: 19666503)
Nat Cell Biol. 2014 Jul;16(7):663-72. (PMID: 24952464)
J Cell Sci. 2021 Jul 1;134(13):. (PMID: 34114033)
J Cell Biol. 2010 Jun 14;189(6):1013-25. (PMID: 20530208)
Protein Sci. 2012 Jul;21(7):996-1005. (PMID: 22544544)
Nature. 2001 May 24;411(6836):439-45. (PMID: 11373668)
Biochim Biophys Acta. 2013 Feb;1834(2):499-507. (PMID: 23128140)
Cell. 1997 Dec 26;91(7):985-94. (PMID: 9428521)
Elife. 2023 Nov 01;12:. (PMID: 37910016)
Nucleic Acids Res. 2016 Jan 4;44(D1):D447-56. (PMID: 26527722)
Nat Struct Mol Biol. 2025 Oct;32(10):1989-1998. (PMID: 40730907)
Cell. 2013 Jul 18;154(2):377-90. (PMID: 23870126)
Mol Biol Cell. 2011 Aug 15;22(16):2912-23. (PMID: 21737692)
Science. 2011 Aug 12;333(6044):883-5. (PMID: 21836017)
Sci Adv. 2026 Jul 17;12(29):eaeg1267. (PMID: 42455938)
Dev Cell. 2019 Jun 3;49(5):711-730.e8. (PMID: 31031197)
Nature. 1999 Dec 16;402(6763):778-84. (PMID: 10617199)
J Am Soc Mass Spectrom. 2025 Feb 05;36(2):416-423. (PMID: 39837577)
Nat Struct Mol Biol. 2024 Dec;31(12):1888-1897. (PMID: 38987455)
Nat Rev Mol Cell Biol. 2020 Jun;21(6):307-326. (PMID: 32107477)
Biophys J. 2025 Oct 7;124(19):3278-3290. (PMID: 40898623)
Nature. 2024 Jun;630(8016):493-500. (PMID: 38718835)
Elife. 2025 Jun 11;13:. (PMID: 40497557)
Protein Sci. 2021 Jan;30(1):70-82. (PMID: 32881101)
PLoS Biol. 2011 Nov;9(11):e1001207. (PMID: 22140358)
Mass Spectrom Rev. 2006 Jan-Feb;25(1):158-70. (PMID: 16208684)
Acta Crystallogr D Biol Crystallogr. 2012 Feb;68(Pt 2):154-9. (PMID: 22281744)
Proc Natl Acad Sci U S A. 2010 May 18;107(20):9240-5. (PMID: 20439720)
Sci Signal. 2009 Jun 23;2(76):ra29. (PMID: 19549984)
Mol Cell. 2005 Aug 19;19(4):449-60. (PMID: 16109370)
Cell. 2009 Nov 13;139(4):802-13. (PMID: 19914172)
Nat Rev Mol Cell Biol. 2025 Feb;26(2):86-103. (PMID: 39394463)
Nat Commun. 2022 Jul 25;13(1):4281. (PMID: 35879313)
Sci Adv. 2025 Mar 14;11(11):eadt5439. (PMID: 40073114)
Nat Cell Biol. 2022 Jul;24(7):1088-1098. (PMID: 35725768)
Curr Biol. 2010 May 25;20(10):939-43. (PMID: 20471270)
Grant Information: R01 GM145651 United States GM NIGMS NIH HHS
Entry Date(s): Date Created: 20260223 Date Completed: 20261020 Latest Revision: 20261020
Update Code: 20261020
PubMed Central ID: PMC12919046
DOI: 10.64898/2026.02.06.704517
PMID: 41727108
Database: MEDLINE
Description
ISSN:2692-8205
DOI:10.64898/2026.02.06.704517