5IFW

Quantitative interaction mapping reveals an extended ubiquitin regulatory domain in ASPL that disrupts functional p97 hexamers and induces cell death

5IFW の概要

• エントリーDOI: 10.2210/pdb5ifw/pdb
• 分子名称: Tether containing UBX domain for GLUT4, Transitional endoplasmic reticulum ATPase, ADENOSINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: aspl, p97, disassembly, hexamer, eubx, signaling protein
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Endomembrane system ; Peripheral membrane protein : Q9BZE9; Cytoplasm, cytosol: P55072
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 111660.54

構造登録者

Roske, Y.,Heinemann, U. (登録日: 2016-02-26, 公開日: 2016-10-26, 最終更新日: 2024-01-10)

主引用文献

Arumughan, A.,Roske, Y.,Barth, C.,Forero, L.L.,Bravo-Rodriguez, K.,Redel, A.,Kostova, S.,McShane, E.,Opitz, R.,Faelber, K.,Rau, K.,Mielke, T.,Daumke, O.,Selbach, M.,Sanchez-Garcia, E.,Rocks, O.,Panakova, D.,Heinemann, U.,Wanker, E.E.
Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers.
Nat Commun, 7:13047-13047, 2016

PubMed Abstract: Interaction mapping is a powerful strategy to elucidate the biological function of protein assemblies and their regulators. Here, we report the generation of a quantitative interaction network, directly linking 14 human proteins to the AAA+ ATPase p97, an essential hexameric protein with multiple cellular functions. We show that the high-affinity interacting protein ASPL efficiently promotes p97 hexamer disassembly, resulting in the formation of stable p97:ASPL heterotetramers. High-resolution structural and biochemical studies indicate that an extended UBX domain (eUBX) in ASPL is critical for p97 hexamer disassembly and facilitates the assembly of p97:ASPL heterotetramers. This spontaneous process is accompanied by a reorientation of the D2 ATPase domain in p97 and a loss of its activity. Finally, we demonstrate that overproduction of ASPL disrupts p97 hexamer function in ERAD and that engineered eUBX polypeptides can induce cell death, providing a rationale for developing anti-cancer polypeptide inhibitors that may target p97 activity.

PubMed: 27762274
DOI: 10.1038/ncomms13047

実験手法

X-RAY DIFFRACTION (3.4 Å)