9n6d

Publication Abstract from PubMed

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 GTPgammaS- 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.

Structural insights into GM4951 as a lipid droplet GTPase regulating hepatic lipid metabolism.,Raj R, Jiang Y, Jha RK, Moresco EMY, Joshi H, Zhang Z, Beutler B Nat Commun. 2025 Dec 12;16(1):11458. doi: 10.1038/s41467-025-66253-2. PMID:41387427^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.