5V4B

Crystal structure of the Skp1-FBXW7-DISC1 complex

5V4B の概要

• エントリーDOI: 10.2210/pdb5v4b/pdb
• 関連するPDBエントリー: 2OVP 2OVQ 2OVR
• 分子名称: S-phase kinase-associated protein 1,S-phase kinase-associated protein 1, F-box/WD repeat-containing protein 7, DISC1 peptide, ... (6 entities in total)
• 機能のキーワード: ubiquitin ligase/psychiatric disorders, transcription-cell c complex, transcription
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Isoform 1: Nucleus, nucleoplasm . Isoform 2: Cytoplasm . Isoform 3: Nucleus, nucleolus : Q969H0
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 69606.64

構造登録者

Li, Y.,Baillie, G.S.,Hao, B. (登録日: 2017-03-08, 公開日: 2017-09-20, 最終更新日: 2024-10-23)

主引用文献

Yalla, K.,Elliott, C.,Day, J.P.,Findlay, J.,Barratt, S.,Hughes, Z.A.,Wilson, L.,Whiteley, E.,Popiolek, M.,Li, Y.,Dunlop, J.,Killick, R.,Adams, D.R.,Brandon, N.J.,Houslay, M.D.,Hao, B.,Baillie, G.S.
FBXW7 regulates DISC1 stability via the ubiquitin-proteosome system.
Mol. Psychiatry, 23:1278-1286, 2018

PubMed Abstract: Disrupted in schizophrenia 1 (DISC1) is a multi-functional scaffolding protein that has been associated with neuropsychiatric disease. The role of DISC1 is to assemble protein complexes that promote neural development and signaling, hence tight control of the concentration of cellular DISC1 in neurons is vital to brain function. Using structural and biochemical techniques, we show for we believe the first time that not only is DISC1 turnover elicited by the ubiquitin proteasome system (UPS) but that it is orchestrated by the F-Box protein, FBXW7. We present the structure of FBXW7 bound to the DISC1 phosphodegron motif and exploit this information to prove that disruption of the FBXW7-DISC1 complex results in a stabilization of DISC1. This action can counteract DISC1 deficiencies observed in neural progenitor cells derived from induced pluripotent stem cells from schizophrenia patients with a DISC1 frameshift mutation. Thus manipulation of DISC1 levels via the UPS may provide a novel method to explore DISC1 function.

PubMed: 28727686
DOI: 10.1038/mp.2017.138

実験手法

X-RAY DIFFRACTION (2.6 Å)