5IFS

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

Summary for 5IFS

• Entry DOI: 10.2210/pdb5ifs/pdb
• Descriptor: Tether containing UBX domain for GLUT4, Transitional endoplasmic reticulum ATPase, ADENOSINE-5'-DIPHOSPHATE, ... (8 entities in total)
• Functional Keywords: aspl, p97, disassembly, eubx, signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Endomembrane system ; Peripheral membrane protein : Q9BZE9; Cytoplasm, cytosol: P55072
• Total number of polymer chains: 4
• Total formula weight: 161196.42

Authors

Roske, Y.,Arumughan, A.,Heinemann, U.,Wanker, E. (deposition date: 2016-02-26, release date: 2016-10-26, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.46 Å)