8UF8
Cryo-EM structure of alpha-Klotho
Summary for 8UF8
| Entry DOI | 10.2210/pdb8uf8/pdb |
| EMDB information | 42186 |
| Descriptor | Klotho (1 entity in total) |
| Functional Keywords | protein binding, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 232634.95 |
| Authors | Schnicker, N.J.,Xu, Z.,Mohammad, A.,Gakhar, L.,Huang, C.L. (deposition date: 2023-10-03, release date: 2024-10-16, Last modification date: 2025-02-26) |
| Primary citation | Schnicker, N.J.,Xu, Z.,Amir, M.,Gakhar, L.,Huang, C.L. Conformational landscape of soluble alpha-klotho revealed by cryogenic electron microscopy. Sci Rep, 15:543-543, 2025 Cited by PubMed 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. PubMed: 39747283DOI: 10.1038/s41598-024-84246-x PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (6.5 Å) |
Structure validation
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