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Structure paper

TitleStructural insights into GM4951 as a lipid droplet GTPase regulating hepatic lipid metabolism.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 11458, Year 2025
Publish dateDec 12, 2025
AuthorsRishi Raj / Yiao Jiang / Rahul Kumar Jha / Eva Marie Y Moresco / Himanshu Joshi / Zhao Zhang / Bruce Beutler /
PubMed AbstractGM4951 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 linksNat Commun / PubMed:41387427 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.51 - 3.31 Å
Structure data

EMDB-49057, PDB-9n6d:
Dimeric structure of GM4951
Method: EM (single particle) / Resolution: 3.03 Å

PDB-9n2q:
Structure of GDP-bound GM4951
Method: X-RAY DIFFRACTION / Resolution: 2.51 Å

PDB-9n2r:
Structure of GTP-bound GM4951
Method: X-RAY DIFFRACTION / Resolution: 2.75 Å

PDB-9n2s:
Structure of GDP-bound GM4951_N86K mutant
Method: X-RAY DIFFRACTION / Resolution: 3.31 Å

PDB-9n2t:
Structure of GDP-bound GM4951_D125G mutant
Method: X-RAY DIFFRACTION / Resolution: 2.6 Å

Chemicals

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

ChemComp-GOL:
GLYCEROL

ChemComp-HOH:
WATER

ChemComp-GSP:
5'-GUANOSINE-DIPHOSPHATE-MONOTHIOPHOSPHATE

ChemComp-MG:
Unknown entry

Source
  • mus musculus (house mouse)
KeywordsLIPID BINDING PROTEIN / Lipid droplet associated protein / GTPase / N86K mutant GM4951 / D125G mutant GM4951 / Lipid droplet associated protein.

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