Assembly, analysis and architecture of atypical ubiquitin chains

Hospenthal, Manuela K.; Freund, Stefan; Komander, David

doi:10.1038/nsmb.2547

Cited by 134 publications

(152 citation statements)

References 69 publications

(121 reference statements)

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“…Exchanging K for A or R has the same effects. Although structural information about Ub conjugates built using K6 is becoming available (14,15), a complete understanding of features that render such conjugates biologically stable remain to be elucidated.…”

mentioning

confidence: 99%

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Liu

Lyu

Chin

et al. 2015

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

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Although the ocular lens shares many features with other tissues, it is unique in that it retains its cells throughout life, making it ideal for studies of differentiation/development. Precipitation of proteins results in lens opacification, or cataract, the major blinding disease. Lysines on ubiquitin (Ub) determine fates of Ub-protein substrates. Information regarding ubiquitin proteasome systems (UPSs), specifically of K6 in ubiquitin, is undeveloped. We expressed in the lens a mutant Ub containing a K6W substitution (K6W-Ub). Protein profiles of lenses that express wild-type ubiquitin (WT-Ub) or K6W-Ub differ by only ∼2%. Despite these quantitatively minor differences, in K6W-Ub lenses and multiple model systems we observed a fourfold Ca2+ elevation and hyperactivation of calpain in the core of the lens, as well as calpain-associated fragmentation of critical lens proteins including Filensin, Fodrin, Vimentin, β-Crystallin, Caprin family member 2, and tudor domain containing 7. Truncations can be cataractogenic. Additionally, we observed accumulation of gap junction Connexin43, and diminished Connexin46 levels in vivo and in vitro. These findings suggest that mutation of Ub K6 alters UPS function, perturbs gap junction function, resulting in Ca2+ elevation, hyperactivation of calpain, and associated cleavage of substrates, culminating in developmental defects and a cataractous lens. The data show previously unidentified connections between UPS and calpain-based degradative systems and advance our understanding of roles for Ub K6 in eye development. They also inform about new approaches to delay cataract and other protein precipitation diseases.

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mentioning

confidence: 99%

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Liu

Lyu

Chin

et al. 2015

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

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“…USPs can only interact with the distal end of this particular ubiquitin chain type and process it sequentially. In contrast, the OTU family protein OTUD3 can cleave such chains at any position (95). Remarkably, the OTU family catalytic domains display a wide diversity in chain preferences, despite a high degree of structural conservation.…”

Section: A Chain Linkage Specificitymentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

359

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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“…These patches are positioned relative to each other in a characteristic manner in distinct ubiquitin polymers. Although ubiquitin chains are dynamic entities, structural analyses, mainly using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, have shown that ubiquitin dimers that are linked to K6, K11, K29, K33 and K48 can form intramolecular interfaces between two ubiquitin moieties (Bremm et al, 2010;Cook et al, 1992;Hospenthal et al, 2013;Kristariyanto et al, 2015a,b;Matsumoto et al, 2010;Michel et al, 2015). In contrast, K63-and M1-linked di-ubiquitin moieties adopt predominantly open conformations with no contact sites except that at the linkage point .…”

Section: Structural Features Of Ubiquitinmentioning

confidence: 99%

Ubiquitin chain diversity at a glance

Akutsu

Đikić

Bremm

2016

Journal of Cell Science

380

367

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Ubiquitin plays an essential role in modulating protein functions, and deregulation of the ubiquitin system leads to the development of multiple human diseases. Owing to its molecular features, ubiquitin can form various homo-and heterotypic polymers on substrate proteins, thereby provoking distinct cellular responses. The concept of multifaceted ubiquitin chains encoding different functions has been substantiated in recent years. It has been established that all possible ubiquitin linkage types are utilized for chain assembly and propagation of specific signals in vivo. In addition, branched ubiquitin chains and phosphorylated ubiquitin molecules have been put under the spotlight recently. The development of novel technologies has provided detailed insights into the structure and function of previously poorly understood ubiquitin signals. In this Cell Science at a Glance article and accompanying poster, we provide an update on the complexity of ubiquitin chains and their physiological relevance.

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Assembly, analysis and architecture of atypical ubiquitin chains

Cited by 134 publications

References 69 publications

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Altered ubiquitin causes perturbed calcium homeostasis, hyperactivation of calpain, dysregulated differentiation, and cataract

Deubiquitylases From Genes to Organism

Ubiquitin chain diversity at a glance

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