6R8F

Cryo-EM structure of the Human BRISC-SHMT2 complex

Summary for 6R8F

• Entry DOI: 10.2210/pdb6r8f/pdb
• EMDB information: 4759
• Descriptor: Lys-63-specific deubiquitinase BRCC36, BRISC complex subunit Abraxas 2, Serine hydroxymethyltransferase, mitochondrial, ... (5 entities in total)
• Functional Keywords: complex, deubiquitylation, ubiquitin, immune signalling, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 290687.78

Authors

Walden, M.,Hesketh, E.,Tian, L.,Ranson, N.A.,Greenberg, R.A.,Zeqiraj, E. (deposition date: 2019-04-01, release date: 2019-06-05, Last modification date: 2024-05-22)

Primary citation

Walden, M.,Tian, L.,Ross, R.L.,Sykora, U.M.,Byrne, D.P.,Hesketh, E.L.,Masandi, S.K.,Cassel, J.,George, R.,Ault, J.R.,El Oualid, F.,Pawlowski, K.,Salvino, J.M.,Eyers, P.A.,Ranson, N.A.,Del Galdo, F.,Greenberg, R.A.,Zeqiraj, E.
Metabolic control of BRISC-SHMT2 assembly regulates immune signalling.
Nature, 570:194-199, 2019

PubMed Abstract: Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 Å. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.

PubMed: 31142841
DOI: 10.1038/s41586-019-1232-1

Experimental method

ELECTRON MICROSCOPY (3.8 Å)