8GBN

Structure of Apo Human SIRT5 P114T Mutant

Summary for 8GBN

• Entry DOI: 10.2210/pdb8gbn/pdb
• Descriptor: NAD-dependent protein deacylase sirtuin-5, mitochondrial, ZINC ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: deacetylase, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 59348.47

Authors

Petrunak, E.M.,Stuckey, J.A. (deposition date: 2023-02-26, release date: 2024-06-05, Last modification date: 2024-06-19)

Primary citation

Yuan, T.,Kumar, S.,Skinner, M.E.,Victor-Joseph, R.,Abuaita, M.,Keijer, J.,Zhang, J.,Kunkel, T.J.,Liu, Y.,Petrunak, E.M.,Saunders, T.L.,Lieberman, A.P.,Stuckey, J.A.,Neamati, N.,Al-Murshedi, F.,Alfadhel, M.,Spelbrink, J.N.,Rodenburg, R.,de Boer, V.C.J.,Lombard, D.B.
Human SIRT5 variants with reduced stability and activity do not cause neuropathology in mice.
Iscience, 27:109991-109991, 2024

PubMed Abstract: SIRT5 is a sirtuin deacylase that removes negatively charged lysine modifications, in the mitochondrial matrix and elsewhere in the cell. In benign cells and mouse models, under basal conditions, the phenotypes of SIRT5 deficiency are quite subtle. Here, we identify two homozygous variants in patients suspected to have mitochondrial disease. Both variants, P114T and L128V, are associated with reduced SIRT5 protein stability and impaired biochemical activity, with no evidence of neomorphic or dominant negative properties. The crystal structure of the P114T enzyme was solved and shows only subtle deviations from wild-type. Via CRISPR-Cas9, we generated a mouse model that recapitulates the human P114T mutation; homozygotes show reduced SIRT5 levels and activity, but no obvious metabolic abnormalities, neuropathology, or other gross phenotypes. We conclude that these human variants most likely represent severe hypomorphs, but are likely not by themselves the primary pathogenic cause of the neuropathology observed in the patients.

PubMed: 38846003
DOI: 10.1016/j.isci.2024.109991

Experimental method

X-RAY DIFFRACTION (2.7 Å)