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| Item Type: | Article |
|---|---|
| Title: | Quantitative interaction mapping reveals an extended UBX domain in ASPL that disrupts functional p97 hexamers |
| Creators Name: | Arumughan, A., Roske, Y., Barth, C., Lleras Forero, L., Bravo-Rodriguez, K., Redel, Al., Kostova, S., McShane, E., Opitz, R., Faelber, K., Rau, K., Mielke, T., Daumke, O., Selbach, M., Sanchez-Garcia, E., Rocks, O., Panáková, D., Heinemann, U. and Wanker, E.E. |
| 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. |
| Keywords: | Brain, Cell Proliferation, X-Ray, Crystallography, Endoplasmic Reticulum-Associated Degradation, HEK293 Cells, Mutation, Fusion, Oncogene Proteins, Peptides, Protein Binding, Protein Domains, Protein Engineering, Protein Interaction Maps, Protein Multimerization, Quaternary, Protein Structure, Recombinant Proteins, Valosin Containing Protein |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 7 |
| Page Range: | 13047 |
| Date: | 20 October 2016 |
| Official Publication: | https://doi.org/10.1038/ncomms13047 |
| PubMed: | View item in PubMed |
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