8T48

The N4BP1 CUE-like domain in complex with linear di-Ubiquitin

8T48 の概要

• エントリーDOI: 10.2210/pdb8t48/pdb
• 分子名称: Di-Ubiquitin, NEDD4-binding protein 1, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: n4bp1, ubiquitin, cue-like, protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 54178.41

構造登録者

Schubert, A.F.,Harris, S.F. (登録日: 2023-06-08, 公開日: 2024-03-13, 最終更新日: 2024-05-29)

主引用文献

Gitlin, A.D.,Maltzman, A.,Kanno, Y.,Heger, K.,Reja, R.,Schubert, A.F.,Wierciszewski, L.J.,Pantua, H.,Kapadia, S.B.,Harris, S.F.,Webster, J.D.,Newton, K.,Dixit, V.M.
N4BP1 coordinates ubiquitin-dependent crosstalk within the I kappa B kinase family to limit Toll-like receptor signaling and inflammation.
Immunity, 57:973-, 2024

PubMed Abstract: The ubiquitin-binding endoribonuclease N4BP1 potently suppresses cytokine production by Toll-like receptors (TLRs) that signal through the adaptor MyD88 but is inactivated via caspase-8-mediated cleavage downstream of death receptors, TLR3, or TLR4. Here, we examined the mechanism whereby N4BP1 limits inflammatory responses. In macrophages, deletion of N4BP1 prolonged activation of inflammatory gene transcription at late time points after TRIF-independent TLR activation. Optimal suppression of inflammatory cytokines by N4BP1 depended on its ability to bind polyubiquitin chains, as macrophages and mice-bearing inactivating mutations in a ubiquitin-binding motif in N4BP1 displayed increased TLR-induced cytokine production. Deletion of the noncanonical IκB kinases (ncIKKs), Tbk1 and Ikke, or their adaptor Tank phenocopied N4bp1 deficiency and enhanced macrophage responses to TLR1/2, TLR7, or TLR9 stimulation. Mechanistically, N4BP1 acted in concert with the ncIKKs to limit the duration of canonical IκB kinase (IKKα/β) signaling. Thus, N4BP1 and the ncIKKs serve as an important checkpoint against over-exuberant innate immune responses.

PubMed: 38697117
DOI: 10.1016/j.immuni.2024.04.004

実験手法

X-RAY DIFFRACTION (2 Å)