| Structural highlights
Function
UBXN6_HUMAN May negatively regulate the ATPase activity of VCP, an ATP-driven segregase that associates with different cofactors to control a wide variety of cellular processes (PubMed:26475856). As a cofactor of VCP, it may play a role in the transport of CAV1 to lysosomes for degradation (PubMed:21822278, PubMed:23335559). It may also play a role in endoplasmic reticulum-associated degradation (ERAD) of misfolded proteins (PubMed:19275885). Together with VCP and other cofactors, it may play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes (PubMed:27753622).[1] [2] [3] [4] [5]
Publication Abstract from PubMed
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.
Structure of the PUB Domain from Ubiquitin Regulatory X Domain Protein 1 (UBXD1) and Its Interaction with the p97 AAA+ ATPase.,Blueggel M, van den Boom J, Meyer H, Bayer P, Beuck C Biomolecules. 2019 Dec 14;9(12). pii: biom9120876. doi: 10.3390/biom9120876. PMID:31847414[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Nagahama M, Ohnishi M, Kawate Y, Matsui T, Miyake H, Yuasa K, Tani K, Tagaya M, Tsuji A. UBXD1 is a VCP-interacting protein that is involved in ER-associated degradation. Biochem Biophys Res Commun. 2009 May 1;382(2):303-8. doi:, 10.1016/j.bbrc.2009.03.012. Epub 2009 Mar 9. PMID:19275885 doi:http://dx.doi.org/10.1016/j.bbrc.2009.03.012
- ↑ Ritz D, Vuk M, Kirchner P, Bug M, Schutz S, Hayer A, Bremer S, Lusk C, Baloh RH, Lee H, Glatter T, Gstaiger M, Aebersold R, Weihl CC, Meyer H. Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations. Nat Cell Biol. 2011 Aug 7;13(9):1116-23. doi: 10.1038/ncb2301. PMID:21822278 doi:http://dx.doi.org/10.1038/ncb2301
- ↑ Kirchner P, Bug M, Meyer H. Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal sorting by the VCP/p97 AAA-ATPase. J Biol Chem. 2013 Mar 8;288(10):7363-72. doi: 10.1074/jbc.M112.429076. Epub 2013 , Jan 19. PMID:23335559 doi:http://dx.doi.org/10.1074/jbc.M112.429076
- ↑ Trusch F, Matena A, Vuk M, Koerver L, Knaevelsrud H, Freemont PS, Meyer H, Bayer P. The N-terminal Region of the Ubiquitin Regulatory X (UBX) Domain-containing Protein 1 (UBXD1) Modulates Interdomain Communication within the Valosin-containing Protein p97. J Biol Chem. 2015 Dec 4;290(49):29414-27. doi: 10.1074/jbc.M115.680686. Epub 2015, Oct 16. PMID:26475856 doi:http://dx.doi.org/10.1074/jbc.M115.680686
- ↑ Papadopoulos C, Kirchner P, Bug M, Grum D, Koerver L, Schulze N, Poehler R, Dressler A, Fengler S, Arhzaouy K, Lux V, Ehrmann M, Weihl CC, Meyer H. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J. 2017 Jan 17;36(2):135-150. doi: 10.15252/embj.201695148. Epub 2016 Oct, 17. PMID:27753622 doi:http://dx.doi.org/10.15252/embj.201695148
- ↑ Blueggel M, van den Boom J, Meyer H, Bayer P, Beuck C. Structure of the PUB Domain from Ubiquitin Regulatory X Domain Protein 1 (UBXD1) and Its Interaction with the p97 AAA+ ATPase. Biomolecules. 2019 Dec 14;9(12). pii: biom9120876. doi: 10.3390/biom9120876. PMID:31847414 doi:http://dx.doi.org/10.3390/biom9120876
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