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

Kim, Su Jin; Cho, Jin Hong; Song, Eun Joo; Kim, Soo Jin; Kim, Ho Min; Lee, Jun Young; Suh, Se Won; Kim, Eunice EunKyeong

doi:10.1074/jbc.m113.523936

Cited by 24 publications

(27 citation statements)

References 48 publications

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“…Recently, we reported that the UBXL domain of OTU1 adopts a ubiquitin-like fold and binds at the interface of two subdomains of the N domain of VCP using the S3/S4 loop from the complex structure of the N domain of VCP and the UBXL domain of OTU1 (Kim et al, 2014). However, our electron-microscopy (EM) results on the full-length proteins show that only one OTU1 binds to a VCP hexamer.…”

Section: Introductioncontrasting

confidence: 45%

Crystallization and preliminary X-ray crystallographic analysis of the complex between the N-D1 domain of VCP fromHomo sapiensand the N domain of OTU1 fromSaccharomyces cerevisiae

Kim

2014

Acta Cryst Sect F

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VCP (valosin-containing protein; also known as p97) plays important roles in many biological processes including the ERAD (endoplasmic reticulumassociated degradation) pathway and its function is governed by binding partners. OTU1 (ovarian tumour domain-containing protein 1) is a recently discovered deubiquitinating enzyme that interacts directly with VCP in the ERAD pathway. In order to understand the interactions between the two proteins, the N-D1 domain of VCP and the UBXL domain of OTU1 were cloned, overexpressed, purified and crystallized. The crystals of the complex diffracted to 3.25 Å resolution and belonged to space group P2 1 , with unit-cell parameters a = 165.45, b = 176.73, c = 165.59 Å , = 120.095 . There are two molecules of the complex in the asymmetric unit with a Matthews coefficient of 2.62 Å 3 Da À1 and a solvent content of 53%.

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Section: Introductioncontrasting

confidence: 45%

Crystallization and preliminary X-ray crystallographic analysis of the complex between the N-D1 domain of VCP fromHomo sapiensand the N domain of OTU1 fromSaccharomyces cerevisiae

Kim

2014

Acta Cryst Sect F

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“…Of these, only the p97 UFD1-NPL4-OTU1 complex has been studied in more detail. In vitro binding and EM studies showed that only one OTU1 molecule is recruited into the p97 UFD1-NPL4 complex [58], thus forming an oligomer with a stoichiometry of 6:1:1 similar to the p97 UFD1-NPL4-FAF1 complex discussed above. However, no hierarchical binding was observed, indicating an independent binding mode and suggesting that hierarchical binding may be restricted to substrate-recruiting cofactors of the UBA-UBX type.…”

Section: Higher Order Assembliesmentioning

confidence: 99%

“…In addition to the UBA-UBX proteins discussed above, the UFD1-NPL4 heterodimer was also found in quaternary complexes with p97 and Otu1/YOD1 [51,58], NUB1L [74] and SelS/VIMP [66]. Of these, only the p97 UFD1-NPL4-OTU1 complex has been studied in more detail.…”

Section: Higher Order Assembliesmentioning

confidence: 99%

“…2B). Recently, the crystal structure of the yeast OTU1 UBXL domain in complex with the N domain of p97 has been solved, thus allowing for a detailed structural comparison of UBXL domains (NPL4, OTU1) and UBX domains (p47, FAF1) [58] (Fig. 2B).…”

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

“…The UBXL domains adopt a structure similar to the UBX domain despite a low sequence identity and the lack of the UBX signature motif [58]. The structure of the UBXL domain of NPL4 has been solved by NMR, and based on chemical shift perturbation analysis a structural model for the N domainÀUBXL complex has been calculated [59] (Fig.…”

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

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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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Structural insights into the interaction of human p97 N‐terminal domain and SHP motif in Derlin‐1 rhomboid pseudoprotease

et al. 2016

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The interaction of the rhomboid pseudoprotease Derlin-1 and p97 is crucial for the retrotranslocation of polyubiquitinated substrates in the endoplasmic reticulum-associated degradation pathway. We report a 2.25 Å resolution structure of the p97 N-terminal domain (p97N) in complex with the Derlin-1 SHP motif. Remarkably, the SHP motif adopts a short, antiparallel β-strand that interacts with the β-sheet of p97N-a site distinct from that to which most p97 adaptor proteins bind. Mutational and biochemical analyses contributed to defining the specific interaction, demonstrating the importance of a highly conserved binding pocket on p97N and a signature motif on SHP. Our findings may also provide insights into the interactions between other SHP-containing proteins and p97N.

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

Cited by 24 publications

References 48 publications

Crystallization and preliminary X-ray crystallographic analysis of the complex between the N-D1 domain of VCP fromHomo sapiensand the N domain of OTU1 fromSaccharomyces cerevisiae

Crystallization and preliminary X-ray crystallographic analysis of the complex between the N-D1 domain of VCP fromHomo sapiensand the N domain of OTU1 fromSaccharomyces cerevisiae

Control of p97 function by cofactor binding

Structural insights into the interaction of human p97 N‐terminal domain and SHP motif in Derlin‐1 rhomboid pseudoprotease

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