Affinity Makes the Difference: Nonselective Interaction of the UBA Domain of Ubiquilin-1 with Monomeric Ubiquitin and Polyubiquitin Chains

Zhang, Daoning; Raasi, Shahri; Fushman, David

doi:10.1016/j.jmb.2007.12.029

Cited by 147 publications

(212 citation statements)

References 67 publications

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“…Upon ubiquitin binding, CSPs were identified throughout helix-1 and -3, but helix-2 was unperturbed. These features agree with the conventional ubiquitin-binding mode of canonical UBA domains (37,38), indicating that it is highly likely that the p62 UBA domain binds ubiquitin in a manner conserved among canonical UBA domains.…”

Section: Resultssupporting

confidence: 70%

“…3B). This result is consistent with complex structures between other UBA domains and ubiquitin, in which helix-1 and helix-3 form major interfaces with ubiquitin (38,40). Thus, our data indicate that the p62 UBA domain in its monomeric state possesses the same fold as the canonical UBA domains and binds to ubiquitin in the conserved manner.…”

Section: Structural Determinants Of Dimerization and Ubiquitinsupporting

confidence: 81%

“…This observation is consistent with the crystal structure of dimeric p62 UBA, in which these regions make up the dimer interface. Canonical UBA domains share two common sequence patterns involved in ubiquitin binding as follows: the MGF motif at L1 loop and the di-leucine motif at the end of ␣3 (38). The MGF motif in the p62 UBA domain displays significant CSPs upon binding to ubiquitin (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Crystal Structure of the Ubiquitin-associated (UBA) Domain of p62 and Its Interaction with Ubiquitin

Isogai

Morimoto

Arita

et al. 2011

Journal of Biological Chemistry

120

113

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p62/SQSTM1/A170 is a multimodular protein that is found in ubiquitin-positive inclusions associated with neurodegenerative diseases. Recent findings indicate that p62 mediates the interaction between ubiquitinated proteins and autophagosomes, leading these proteins to be degraded via the autophagy-lysosomal pathway. This ubiquitin-mediated selective autophagy is thought to begin with recognition of the ubiquitinated proteins by the C-terminal ubiquitin-associated (UBA) domain of p62. We present here the crystal structure of the UBA domain of mouse p62 and the solution structure of its ubiquitin-bound form. The p62 UBA domain adopts a novel dimeric structure in crystals, which is distinctive from those of other UBA domains. NMR analyses reveal that in solution the domain exists in equilibrium between the dimer and monomer forms, and binding ubiquitin shifts the equilibrium toward the monomer to form a 1:1 complex between the UBA domain and ubiquitin. The dimer-to-monomer transition is associated with a structural change of the very C-terminal end of the p62 UBA domain, although the UBA fold itself is essentially maintained. Our data illustrate that dimerization and ubiquitin binding of the p62 UBA domain are incompatible with each other. These observations reveal an autoinhibitory mechanism in the p62 UBA domain and suggest that autoinhibition plays a role in the function of p62.Impairment of the ubiquitin-proteasome system is one of major causes of ubiquitin-positive inclusions found in various neurodegenerative diseases (1). Recent studies have identified the involvement of another degradation system, the autophagy-lysosomal pathway, in the formation of ubiquitin-positive inclusions as exemplified by the observation that autophagy-deficient mice exhibit substantial accumulation of such inclusions in tissues (2). p62/SQSTM1/A170, a multidomain protein found in ubiquitin-positive inclusions, has been shown to bind intracellular signaling factors (3-5). Accumulating evidence indicates that p62 is a receptor for ubiquitinated proteins that are targeted to the autophagosome for lysosomal degradation. Specifically, it is involved in autophagic elimination of damaged mitochondria, midbody rings, peroxisomes, and microbes (6 -10).The importance of p62 in autophagic degradation of proteins and organelles has been demonstrated by studies using tissuespecific autophagy-deficient mice. Elimination of Atg5 or Atg7, an essential gene in the formation of the autophagosome, in mouse neurons and hepatocytes resulted in toxicity accompanied by accumulation of ubiquitin-positive inclusions in the cells. In contrast, knock-out of both Atg7 and p62 (Atg7 Ϫ/Ϫ / p62 Ϫ/Ϫ ) caused a dramatic reduction in the amount of inclusions in both types of cells (2, 11). A similar result was also reported in fruit flies (12). These observations indicate that p62 is critically involved in the development of ubiquitin-positive inclusions that should be degraded via autophagy. In addition to playing a role in the autophagy-lysosomal pathway, p62 its...

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Section: Resultssupporting

confidence: 70%

Section: Structural Determinants Of Dimerization and Ubiquitinsupporting

confidence: 81%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Crystal Structure of the Ubiquitin-associated (UBA) Domain of p62 and Its Interaction with Ubiquitin

Isogai

Morimoto

Arita

et al. 2011

Journal of Biological Chemistry

120

113

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“…3A) (16)(17)(18). The domain structure and previous literature on Ubqln suggest that it interacts with ubiquitinated proteins through its UBA domain and with the proteasome through its UBL domain (19,20). Based on these interactions, Ubqln is thought to serve as a bridge between ubiquitinated proteins and the proteasome to facilitate degradation of the ubiquitinated targets.…”

mentioning

confidence: 99%

Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1

Beverly

Lockwood

Shah

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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We have previously shown that all six members of the anti-apoptotic BCL2 gene family can cooperate with (myelocytomatosis oncogene) MYC in a mouse model of leukemia, but three of them are significantly less potent contributors to leukemogenicity than the other three. The protein encoded by one of these less potent genes, BCL2L10∕BCLb, was recently shown to vary dramatically in many primary human cancers by immunohistochemistry, and the protein levels were inversely correlated with survival in patients with several cancer types. We examined BCLb mRNA in a panel of human cancer cell lines and did not observe the extensive variation in mRNA that would be required to explain the vast differences in protein levels. We found that the levels of BCLb protein diminish quickly after inhibition of protein synthesis with cycloheximide, so we searched for interacting proteins that might affect posttranslational stability of BCLb. Using a variety of approaches, including immunoaffinity and mass spectrometry, we identified a protein, Ubiquilin1 (Ubqln), that specifically interacts with BCLb, and not with other anti-apoptotic BCL2-like proteins. Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. Furthermore, primary lung adencarcinomas have more Ubqln mRNA than normal adjacent lung tissue, and higher Ubqln mRNA levels are associated with shorter survival of lung cancer patients, suggesting that potentiation of the anti-apoptotic potential of BCLb through regulation of its stability by Ubqln may be an important factor in tumor progression.

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“…or linear [104][105][106][107][108]. A large study by Raasi and coworkers pinpointed the specificity of 30 of these domains [109].…”

Section: Tandem Ubiquitin Binding Entity (Tube) Based Enrichmentmentioning

confidence: 99%

Proteomic techniques to probe the ubiquitin landscape

2015

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Affinity Makes the Difference: Nonselective Interaction of the UBA Domain of Ubiquilin-1 with Monomeric Ubiquitin and Polyubiquitin Chains

Cited by 147 publications

References 67 publications

Crystal Structure of the Ubiquitin-associated (UBA) Domain of p62 and Its Interaction with Ubiquitin

Crystal Structure of the Ubiquitin-associated (UBA) Domain of p62 and Its Interaction with Ubiquitin

Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1

Proteomic techniques to probe the ubiquitin landscape

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