Journal article
Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy
Scientific reports, Vol.15(1), 543
01/02/2025
DOI: 10.1038/s41598-024-84246-x
PMCID: PMC11696049
PMID: 39747283
Abstract
α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23. To understand the FGFR/FGF23-independent pleiotropic functions of sKLA, we investigated biophysical properties and structure of apo-sKLA. Single particle cryogenic electron microscopy (cryo-EM) revealed a 3.3 Å resolution structure of apo-sKLA that overlays well with its counterpart in the ternary complex with several distinct features. Compared to the ternary complex, the KL2 domain of apo-sKLA is more flexible. Three-dimensional variability analysis revealed that apo-sKLA adopts conformations with different KL1-KL2 interdomain bending and rotational angles. Mass photometry revealed that sKLA can form a stable structure with FGFR and/or FGF23 as well as sKLA dimer in solution. Cryo-EM supported the dimeric structure of sKLA. Recent studies revealed that FGF23 contains two KLA-binding sites. Our computational studies revealed that each site binds separate KLA in the dimer. The potential multiple forms and shapes of sKLA support its role as FGFR-independent hormone with pleiotropic functions. The ability of FGF23 to engage two KLA's simultaneously raises a potential new mechanism of action for FGF23-mediated signaling by the membranous klotho.
Details
- Title: Subtitle
- Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy
- Creators
- Nicholas J Schnicker - University of IowaZhen Xu - University of IowaMohammad Amir - University of IowaLokesh Gakhar - University of IowaChou-Long Huang - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. chou-long-huang@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Scientific reports, Vol.15(1), 543
- DOI
- 10.1038/s41598-024-84246-x
- PMID
- 39747283
- PMCID
- PMC11696049
- NLM abbreviation
- Sci Rep
- ISSN
- 2045-2322
- eISSN
- 2045-2322
- Publisher
- NATURE PORTFOLIO
- Grant note
- DK100605 / NIDDK NIH HHS
- Language
- English
- Date published
- 01/02/2025
- Academic Unit
- Molecular Physiology and Biophysics; Nephrology; Medicine Administration; Internal Medicine
- Record Identifier
- 9984770792502771
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