Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy

Nicholas J Schnicker; Zhen Xu; Mohammad Amir; Lokesh Gakhar; Chou-Long Huang

doi:10.1101/2024.03.02.583144

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Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy

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Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy

Nicholas J Schnicker, Zhen Xu, Mohammad Amir, Lokesh Gakhar and Chou-Long Huang

bioRxiv : the preprint server for biology

03/06/2024

DOI: 10.1101/2024.03.02.583144

PMCID: PMC10942382

PMID: 38496408

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https://doi.org/10.1101/2024.03.02.583144View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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. Mass photometry revealed that sKLA can form a stable structure with FGFR and/or FGF23 as well as sKLA dimer in solution. Single particle cryogenic electron microscopy (cryo-EM) supported the dimeric structure of sKLA. Cryo-EM further revealed a 3.3Å 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. 3D variability analysis revealed that apo-sKLA adopts conformations with different KL1-KL2 interdomain bending and rotational angles. The potential multiple forms and shapes of sKLA support its role as FGFR-independent hormone with pleiotropic functions. A comprehensive understanding of the sKLA conformational landscape will provide the foundation for developing klotho-related therapies for diseases.

Fibroblast growth factor (FGF)

monomer

Soluble alpha-klotho (sKLA)

dimer

ternary complex

3D variability analysis (3DVA)

cryogenic electron microscopy (cryo-EM)

Details

Title: Subtitle: Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy
Creators: Nicholas J Schnicker - University of Iowa
Zhen Xu - University of Iowa
Mohammad Amir - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, 52242, USA
Lokesh Gakhar - University of Iowa
Chou-Long Huang - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv : the preprint server for biology
DOI: 10.1101/2024.03.02.583144
PMID: 38496408
PMCID: PMC10942382
Publisher: United States
Grant note: P50 HD103556 / NICHD NIH HHS R01 DK100605 / NIDDK NIH HHS U24 GM129547 / NIGMS NIH HHS R01 DK109887 / NIDDK NIH HHS
Language: English
Date posted: 03/06/2024
Academic Unit: Molecular Physiology and Biophysics; Nephrology; Medicine Administration; Internal Medicine
Record Identifier: 9984577124202771

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