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| Title | Structural insights into GM4951 as a lipid droplet GTPase regulating hepatic lipid metabolism. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 16, Issue 1, Page 11458, Year 2025 |
| Publish date | Dec 12, 2025 |
Authors | Rishi Raj / Yiao Jiang / Rahul Kumar Jha / Eva Marie Y Moresco / Himanshu Joshi / Zhao Zhang / Bruce Beutler / ![]() |
| PubMed Abstract | GM4951 is an immunity-related GTPase (IRG) that counteracts hepatic lipid accumulation in mice fed a high-fat diet. We determine full-length protein structures of GTPγS- and GDP-bound GM4951, and ...GM4951 is an immunity-related GTPase (IRG) that counteracts hepatic lipid accumulation in mice fed a high-fat diet. We determine full-length protein structures of GTPγS- and GDP-bound GM4951, and two missense mutants (N86K or D125G) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) in mice. All four structures reveal a conserved GTPase domain fold and a helix bundle composed of the N- and C-terminal regions. Each mutation alters the dynamics of the switch-I and switch-II loops important for catalytic function and lipid droplet (LD) localization. GM4951 predominantly forms dimers in vitro. Cryo-electron microscopy reveals a dimer interface formed by the helical domains of two protomers (tail to tail), distinct from other IRGs. The N-terminal helices are necessary for LD localization, while a disulfide bond between helices in the GTPase domain and C-terminus is necessary for interaction with MASLD-associated HSD17B13. Distinct N- and C-terminal conformations set GM4951 apart from other IRGs structurally and functionally. |
External links | Nat Commun / PubMed:41387427 / PubMed Central |
| Methods | EM (single particle) / X-ray diffraction |
| Resolution | 2.51 - 3.31 Å |
| Structure data | EMDB-49057, PDB-9n6d: ![]() PDB-9n2q: ![]() PDB-9n2r: ![]() PDB-9n2s: ![]() PDB-9n2t: |
| Chemicals | ![]() ChemComp-GDP: ![]() ChemComp-GOL: ![]() ChemComp-HOH: ![]() ChemComp-GSP: ![]() ChemComp-MG: |
| Source |
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Keywords | LIPID BINDING PROTEIN / Lipid droplet associated protein / GTPase / N86K mutant GM4951 / D125G mutant GM4951 / Lipid droplet associated protein. |
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