Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism

Cappadocia, Laurent; Lima, Christopher D.

doi:10.1021/acs.chemrev.6b00737

Cited by 436 publications

(429 citation statements)

References 281 publications

(817 reference statements)

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“…Both types of ubiquitination are involved in regulating the signaling that directs the antiviral innate immune response [7,8]. Additional Ublike (UBL) proteins such as SUMO or NEDD8 are structured around a β-grasp fold and possess a Cterminal diGly motif similar to Ub, which allows for covalent conjugation to substrates by their respective E1, E2, and E3 enzymes [9][10][11]. In contrast, the UBL protein interferon (IFN)-stimulated gene (ISG) 15 (ISG15) is composed of two tandem UBL folds that are connected by a short linker; however, it retains the distinctive diGly motif at its C terminus for attachment to target proteins (Fig.…”

Section: Viruses and The Ub Systemmentioning

confidence: 99%

Structure and Function of Viral Deubiquitinating Enzymes

Bailey-Elkin

Knaap

Kikkert

et al. 2017

Journal of Molecular Biology

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Post-translational modification of cellular proteins by ubiquitin regulates numerous cellular processes, including innate and adaptive immune responses. Ubiquitin-mediated control over these processes can be reversed by cellular deubiquitinating enzymes (DUBs), which remove ubiquitin from cellular targets and depolymerize polyubiquitin chains. The importance of protein ubiquitination to host immunity has been underscored by the discovery of viruses that encode proteases with deubiquitinating activity, many of which have been demonstrated to actively corrupt cellular ubiquitin-dependent processes to suppress innate antiviral responses and promote viral replication. DUBs have now been identified in diverse viral lineages, and their characterization is providing valuable insights into virus biology and the role of the ubiquitin system in host antiviral mechanisms. Here, we provide an overview of the structural biology of these fascinating viral enzymes and their role innate immune evasion and viral replication.

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Section: Viruses and The Ub Systemmentioning

confidence: 99%

Structure and Function of Viral Deubiquitinating Enzymes

Bailey-Elkin

Knaap

Kikkert

et al. 2017

Journal of Molecular Biology

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“…Unlike Ub (8 kDa), SUMO proteins have an N‐terminal flexible extension, which makes them significantly larger (11 kDa). SUMOylation is directed by an enzymatic cascade analogous to ubiquitination and SUMO is generally conjugated onto lysine residues of target proteins 4. SUMO has 3 active isoforms, SUMO‐1, ‐2 and ‐3, with mature SUMO‐2 and ‐3 being virtually identical 5.…”

mentioning

confidence: 99%

“…In contrast to ubiquitin chains, where linkages through all seven lysine residues have been observed, one type of SUMO chain—linked through lysine 11 of SUMO‐2/3—appears to predominate 4. Since SUMO‐2/3 show a high degree of sequence similarity, we chose to focus on a K11 diSUMO‐2 vinylamide (VA) suicide version that can bind covalently.…”

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confidence: 99%

Total Chemical Synthesis of SUMO and SUMO‐Based Probes for Profiling the Activity of SUMO‐Specific Proteases

et al. 2018

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SUMO is a post‐translational modifier critical for cell cycle progression and genome stability that plays a role in tumorigenesis, thus rendering SUMO‐specific enzymes potential pharmacological targets. However, the systematic generation of tools for the activity profiling of SUMO‐specific enzymes has proven challenging. We developed a diversifiable synthetic platform for SUMO‐based probes by using a direct linear synthesis method, which permits N‐ and C‐terminal labelling to incorporate dyes and reactive warheads, respectively. In this manner, activity‐based probes (ABPs) for SUMO‐1, SUMO‐2, and SUMO‐3‐specific proteases were generated and validated in cells using gel‐based assays and confocal microscopy. We further expanded our toolbox with the synthesis of a K11‐linked diSUMO‐2 probe to study the proteolytic cleavage of SUMO chains. Together, these ABPs demonstrate the versatility and specificity of our synthetic SUMO platform for in vitro and in vivo characterization of the SUMO protease family.

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“…In addition, it has been suggested that modification of activating signal cointegrator 1 by UFM1 is involved in development of ER + breast cancer (9). To modify a protein with UFM1, a 3-enzyme cascade is required (10)(11)(12), similar to ubiquitin and other UBLs. First, the activating enzyme (E1)ubiquitin like modifier activating enzyme 5 (UBA5)hydrolyzes ATP and forms a thioester bond between the UFM1 C terminus and its active site cysteine.…”

mentioning

confidence: 99%

Trans ‐binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP binding

Mashahreh¹,

Hassouna²,

Soudah³

et al. 2018

FASEB j.

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All ubiquitin-like proteins (UBLs) undergo an activation process before their conjugation to target proteins. Although the steps required for the activation of UBLs are conserved and common to all UBLs, we have previously shown that the activation of the UBL, ubiquitin fold modifier 1 (UFM1) by the E1, Ufm1 modifier-activating enzyme 5 (UBA5) is executed in a trans-binding mechanism, not observed in any other E1. In this study, we explored the necessity of that mechanism for UFM1 activation and found that it is needed not only for UFM1 binding to UBA5 but also for stabilizing the UBA5 homodimer. Although UBA5 functions as a dimer, in solution it behaves as a weak dimer. Dimerization of UBA5 is required for ATP binding; therefore, stabilization of the dimer by UFM1 enhances ATP binding. Our results make a connection between the binding of UFM1 to UBA5 and the latter's affinity to ATP, so we propose a novel mechanism for the regulation of ATP's binding to E1.-Mashahreh, B., Hassouna, F., Soudah, N., Cohen-Kfir, E., Strulovich, R., Haitin, Y., Wiener, R. Trans-binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP binding.

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Ubiquitin-like Protein Conjugation: Structures, Chemistry, and Mechanism

Cited by 436 publications

References 281 publications

Structure and Function of Viral Deubiquitinating Enzymes

Structure and Function of Viral Deubiquitinating Enzymes

Total Chemical Synthesis of SUMO and SUMO‐Based Probes for Profiling the Activity of SUMO‐Specific Proteases

Trans ‐binding of UFM1 to UBA5 stimulates UBA5 homodimerization and ATP binding

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