Structure of the PUB Domain from Ubiquitin Regulatory X Domain Protein 1 (UBXD1) and Its Interaction with the p97 AAA+ ATPase

GND
1205410856
ORCID
0000-0002-8963-256X
LSF
60823
Affiliation
University of Duisburg-Essen, Structural and Medicinal Biochemistry, Centre for Medical Biotechnology (ZMB), 45117 Essen, Germany.
Blüggel, Mike;
GND
1075564441
LSF
52565
Affiliation
University of Duisburg-Essen, Molecular Biology, 45117 Essen, Germany.
Boom, Johannes van den;
GND
1089446616
LSF
51479
Affiliation
University of Duisburg-Essen, Molecular Biology, 45117 Essen, Germany.
Meyer, Hemmo;
GND
1059319691
ORCID
0000-0003-0435-7202
LSF
10134
Affiliation
University of Duisburg-Essen, Structural and Medicinal Biochemistry, Centre for Medical Biotechnology (ZMB), 45117 Essen, Germany.
Bayer, Peter;
GND
114677186X
ORCID
0000-0001-7513-7384
LSF
56731
Affiliation
University of Duisburg-Essen, Structural and Medicinal Biochemistry, Centre for Medical Biotechnology (ZMB), 45117 Essen, Germany.
Beuck, Christine

AAA+ ATPase p97/valosin-containing protein (VCP)/Cdc48 is a key player in various cellular stress responses in which it unfolds ubiquitinated proteins to facilitate their degradation by the proteasome. P97 works in different cellular processes using alternative sets of cofactors and is implicated in multiple degenerative diseases. Ubiquitin regulatory X domain protein 1 (UBXD1) has been linked to pathogenesis and is unique amongst p97 cofactors because it interacts with both termini of p97. Its N-domain binds to the N-domain and N/D1 interface of p97 and regulates its ATPase activity. The PUB (peptide:N-glycanase and UBA or UBX-containing proteins) domain binds the p97 C-terminus, but how it controls p97 function is still unknown. Here we present the NMR structure of UBXD1-PUB together with binding studies, mutational analysis, and a model of UBXD1-PUB in complex with the p97 C-terminus. While the binding pocket is conserved among PUB domains, UBXD1-PUB features a unique loop and turn regions suggesting a role in coordinating interaction with downstream regulators and substrate processing.

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Blueggel, M., van den Boom, J., Meyer, H., Bayer, P., Beuck, C., 2019. Structure of the PUB Domain from Ubiquitin Regulatory X Domain Protein 1 (UBXD1) and Its Interaction with the p97 AAA+ ATPase. https://doi.org/10.3390/biom9120876
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