UBXD1 binds p97 through two independent binding sites

Kern, Maximilian J; Fernández‐Sáiz, Vanesa; Schäfer, Zasie; Buchberger, Alexander

doi:10.1016/j.bbrc.2009.01.076

Cited by 37 publications

(86 citation statements)

References 22 publications

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“…The shp1-eyc-p47 domain is reported to form a trimer and binds at the interface between the N and D1 domains of VCP. Besides the hierarchical binding of VCP-binding partners, some binding partners such as UFD1/NPL4, p47, and UBXD1 are reported to show mutually exclusive binding (46,47), whereas others such as UFD1/NPL4 and UBX4 show simultaneous binding (48). This is understandable considering the existence of numerous binding partners and the diverse functions of VCP.…”

Section: Resultsmentioning

confidence: 96%

Structural Basis for Ovarian Tumor Domain-containing Protein 1 (OTU1) Binding to p97/Valosin-containing Protein (VCP)

Kim

Cho

Song

et al. 2014

Journal of Biological Chemistry

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Background: Ovarian tumor domain-containing protein 1 (OTU1) acts as a deubiquitinating enzyme in the endoplasmic reticulum-associated degradation (ERAD) pathway by associating with valosin-containing protein (VCP). Results: One OTU1 binds to a VCP hexamer with a K D of 0.71 M. Conclusion:The 39 GYPP 42 (S3/S4) loop of OTU1 is critical for interaction with VCP. Significance: This is the first structural study of VCP and OTU1 complex.

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Section: Resultsmentioning

confidence: 96%

Structural Basis for Ovarian Tumor Domain-containing Protein 1 (OTU1) Binding to p97/Valosin-containing Protein (VCP)

Kim

Cho

Song

et al. 2014

Journal of Biological Chemistry

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“…Three PUB-domain containing proteins have been described so far in humans and all interact with the p97 C-terminal tail: PNGase (peptide N-glycanase) [85,86], which is involved in the deglycosylation of misfolded glycoproteins [87], the UBX protein UBXD1 [68,85,88], and HOIP (HOIL-1-interacting protein) [89][90][91], the catalytic subunit of the E3 ubiquitin ligase LUBAC, which catalyzes the assembly of linear ubiquitin chains [92]. Molecular insights into the interaction of the PUB domain with p97 were revealed by crystal structures of the PNGase and HOIP PUB domains in complex with peptides comprising the five and four, respectively, C-terminal residues of p97 called PIM (PUB Interacting Motif) [86,91] (Fig.…”

Section: The Pub Domainmentioning

confidence: 99%

Control of p97 function by cofactor binding

2015

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Edited by Wilhelm JustKeywords: ATPases Associated with diverse cellular Activities p47 UFD1-NPL4 UBXD1 Inclusion Body Myopathy with Pagets disease of the bone and Fronto-temporal Dementia a b s t r a c t p97 (also known as Cdc48, Ter94, and VCP) is an essential, abundant and highly conserved ATPase driving the turnover of ubiquitylated proteins in eukaryotes. Even though p97 is involved in highly diverse cellular pathways and processes, it exhibits hardly any substrate specificity on its own. Instead, it relies on a large number of regulatory cofactors controlling substrate specificity and turnover. The complexity as well as temporal and spatial regulation of the interactions between p97 and its cofactors is only beginning to be understood at the molecular level. Here, we give an overview on the structural framework of p97 interactions with its cofactors, the emerging principles underlying the assembly of complexes with different cofactors, and the pathogenic effects of disease-associated p97 mutations on cofactor binding.

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“…Plasmids for the bacterial expression of glutathione S-transferase (GST) fusion proteins of yeast Ufd2 and Ufd3 (56), human E4B (15), the PUB domain of human PNGase (1), and the UBX domain of Shp1 (59), for the bacterial expression of hexahistidine fusion proteins of full-length p97 and p97⌬N lacking residues 1 to 199 (33), for the expression of Gal4 activation domain fusions of Ufd2 (35) and Ufd3 (56) in yeast, and for the galactoseinducible expression of Ub-P-␤-Gal (4) and GST-His 6 -Pex29 (40) in yeast have been described previously.…”

Section: Plasmidsmentioning

confidence: 99%

“…Cells were lysed in buffer C (50 mM HEPES [pH 7.5], 5 mM EDTA, 150 mM NaCl, 1% Triton X-100, 2 mM PMSF, complete protease inhibitor cocktail) using glass beads, and extracts were incubated with 20 l glutathione-Sepharose 4B (GE Healthcare). Glutathione-Sepharose pulldown experiments were performed as described previously (33), and bound material was eluted by heating in HU buffer (34). GST-His 6 -Pex29 was detected by Western blot analysis and quantified as described above.…”

Section: Plasmidsmentioning

confidence: 99%

Cellular Functions of Ufd2 and Ufd3 in Proteasomal Protein Degradation Depend on Cdc48 Binding

Böhm

Lamberti

Fernández‐Sáiz

et al. 2011

Molecular and Cellular Biology

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The chaperone-related AAA ATPase Cdc48 (p97/VCP in higher eukaryotes) segregates ubiquitylated proteins for subsequent degradation by the 26S proteasome or for nonproteolytic fates. The specific outcome of Cdc48 activity is controlled by the evolutionary conserved cofactors Ufd2 and Ufd3, which antagonistically regulate the substrates' ubiquitylation states. In contrast to the interaction of Ufd3 and Cdc48, the interaction between the ubiquitin chain elongating enzyme Ufd2 and Cdc48 has not been precisely mapped. Consequently, it is still unknown whether physiological functions of Ufd2 in fact require Cdc48 binding. Here, we show that Ufd2 binds to the C-terminal tail of Cdc48, unlike the human Ufd2 homologue E4B, which interacts with the N domain of p97. The binding sites for Ufd2 and Ufd3 on Cdc48 overlap and depend critically on the conserved residue Y834 but are not identical. Saccharomyces cerevisiae cdc48 mutants altered in residue Y834 or lacking the C-terminal tail are viable and exhibit normal growth. Importantly, however, loss of Ufd2 and Ufd3 binding in these mutants phenocopies defects of ⌬ufd2 and ⌬ufd3 mutants in the ubiquitin fusion degradation (UFD) and Ole1 fatty acid desaturase activation (OLE) pathways. These results indicate that key cellular functions of Ufd2 and Ufd3 in proteasomal protein degradation require their interaction with Cdc48.

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UBXD1 binds p97 through two independent binding sites

Cited by 37 publications

References 22 publications

Structural Basis for Ovarian Tumor Domain-containing Protein 1 (OTU1) Binding to p97/Valosin-containing Protein (VCP)

Structural Basis for Ovarian Tumor Domain-containing Protein 1 (OTU1) Binding to p97/Valosin-containing Protein (VCP)

Control of p97 function by cofactor binding

Cellular Functions of Ufd2 and Ufd3 in Proteasomal Protein Degradation Depend on Cdc48 Binding

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