6R8F

Cryo-EM structure of the Human BRISC-SHMT2 complex

6R8F の概要

• エントリーDOI: 10.2210/pdb6r8f/pdb
• EMDBエントリー: 4759
• 分子名称: Lys-63-specific deubiquitinase BRCC36, BRISC complex subunit Abraxas 2, Serine hydroxymethyltransferase, mitochondrial, ... (5 entities in total)
• 機能のキーワード: complex, deubiquitylation, ubiquitin, immune signalling, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 290687.78

構造登録者

Walden, M.,Hesketh, E.,Tian, L.,Ranson, N.A.,Greenberg, R.A.,Zeqiraj, E. (登録日: 2019-04-01, 公開日: 2019-06-05, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.8 Å)