5ifs
From Proteopedia
Quantitative interaction mapping reveals an extended ubiquitin regulatory domain in ASPL that disrupts functional p97 hexamers and induces cell death
Structural highlights
DiseaseASPC1_HUMAN Translocation renal cell carcinoma;Alveolar soft-tissue sarcoma. A chromosomal aberration involving ASPSCR1 is found in patients with alveolar soft part sarcoma. Translocation t(X;17)(p11;q25) with TFE3 forms a ASPSCR1-TFE3 fusion protein.[1] A chromosomal aberration involving ASPSCR1 has been found in two patients with of papillary renal cell carcinoma. Translocation t(X;17)(p11.2;q25).[2] FunctionASPC1_HUMAN Tethering protein that sequesters GLUT4-containing vesicles in the cytoplasm in the absence of insulin. Modulates the amount of GLUT4 that is available at the cell surface (By similarity). Enhances VCP methylation catalyzed by VCPKMT.[3] Publication Abstract from PubMedInteraction 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. Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers.,Arumughan A, Roske Y, Barth C, Forero LL, 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 EE Nat Commun. 2016 Oct 20;7:13047. doi: 10.1038/ncomms13047. PMID:27762274[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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