Mechanism of Lys6 poly-ubiquitin specificity by the <i>L. pneumophila</i> deubiquitinase LotA

Warren, Gus D; Kitao, Tomoe; Franklin, Tyler G.; Nguyen, Justine; Geurink, Paul P.; Kubori, Tomoko; Nagai, Hiroki; Pruneda, Jonathan N.

doi:10.1101/2022.05.11.491541

Cited by 3 publications

(3 citation statements)

References 80 publications

(148 reference statements)

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“…Therefore, our results indicate that the helical loop present toward the C-terminal from the CR is the VR1 of the Lot family, and it forms a part of the S1 ubiquitin-binding site. It is worth noting that similar findings on LotA are reported, whereas our article was under review ( Warren et al, 2022 Preprint ). Consistent with our finding, the crystal structure of LotA in complex with ubiquitin showed the VR1 of LotA to be crucial for ubiquitin binding to LotA.…”

Section: Resultssupporting

confidence: 82%

Structural insights into ubiquitin chain cleavage byLegionellaovarian tumor deubiquitinases

et al. 2023

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Although ubiquitin is found only in eukaryotes, several pathogenic bacteria and viruses possess proteins that hinder the host ubiquitin system.Legionella, a gram-negative intracellular bacterium, possesses an ovarian tumor (OTU) family of deubiquitinases (Lot DUBs). Herein, we describe the molecular characteristics of Lot DUBs. We elucidated the structure of the LotA OTU1 domain and revealed that entire Lot DUBs possess a characteristic extended helical lobe that is not found in other OTU-DUBs. The structural topology of an extended helical lobe is the same throughout the Lot family, and it provides an S1′ ubiquitin-binding site. Moreover, the catalytic triads of Lot DUBs resemble those of the A20-type OTU-DUBs. Furthermore, we revealed a unique mechanism by which LotA OTU domains cooperate together to distinguish the length of the chain and preferentially cleave longer K48-linked polyubiquitin chains. The LotA OTU1 domain itself cleaves K6-linked ubiquitin chains, whereas it is also essential for assisting the cleavage of longer K48-linked polyubiquitin chains by the OTU2 domain. Thus, this study provides novel insights into the structure and mechanism of action of Lot DUBs.

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Section: Resultssupporting

confidence: 82%

Structural insights into ubiquitin chain cleavage byLegionellaovarian tumor deubiquitinases

et al. 2023

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“…Thus, a possibly indirect role of the α9-helix in K6-recognition cannot be excluded. In a recent study on the K6-speci c DUB LotA, an interaction between the Ile36 and Ile44 patches of two adjacent K6-linked ubiquitin moieties was reported, which had to be dissolved by the enzyme before cleaving the isopeptide bond 54 . It is possible that the α9-helix of Wc-VTD1 ful lls a similar task.…”

Section: Discussionmentioning

confidence: 99%

“…K6-linked ubiquitin chains have been implicated in various biological processes including DNA damage and mitophagy [7][8][9] , but the particular role of this linkage type is insu ciently understood 6 . The only known example of a truly K6-speci c deubiquitinase is the bacterial effector LotA from Legionella pneumophila, whose N-terminal OTU domain harbors this activity 14,54 . Waddlia chrondophila is unrelated to Legionella, but has a similar intracellular lifestyle within bacteria-containing vacuoles.…”

Section: Discussionmentioning

confidence: 99%

A new family of eukaryotic and bacterial deubiquitinases spreading and diversifying through transposons and horizontal gene transfer

Erven

Abraham

Hermanns

et al. 2022

Preprint

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Several distinct families of eukaryotic deubiquitinases (DUBs) regulate various aspects of ubiquitin signaling. Apart from one metalloenzyme family, six classes of eukaryotic papain-fold cysteine proteases are known to have DUB activity. A seventh cysteine-based DUB class is found in intracellular bacteria, which use DUB effectors to evade the ubiquitin-based defense response. Here, we report on the presence of an additional DUB class broadly distributed in eukaryotes and several bacteria. So far, the only known members of this family are the large tegument proteins of α/β/γ herpesviruses, which act as relatively unspecific deubiquitinases and deneddylases attached to the outer face of the viral capsid. By using a bioinformatical screen, we identified distant homologs of this family in transposons of vertebrates and invertebrates, in agaricomycete fungi, insects, nematodes, cnidaria, protists and selected intracellular bacteria. Members of this VTD (Viral tegument-like DUB) family use an atypical Cys-Asp-His catalytic triad to cleave ubiquitin chains. Some activities resemble the viral tegument DUBs in preferring K48-linked ubiquitin chains and also cleaving NEDD8, while other members are highly specific for K6- or K63-linked ubiquitin chains. Judging by the crystal structures of K48- and K6-specific members, the subfamilies differ considerably in their ubiquitin recognition mode. Our analyses suggest that this deubiquitinase family evolved from YopT/HopN-like non-DUB proteases and was co-opted early by DNA transposons, helping the spread of this family. In several independent events, the deubiquitinase domain of these transposons was ‘domesticated’ by various taxa, giving rise e.g. to the Drosophila male sterile (3)76Ca gene and several nematode genes with male-specific expression.

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A widely distributed family of eukaryotic and bacterial deubiquitinases related to herpesviral large tegument proteins

et al. 2022

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Distinct families of eukaryotic deubiquitinases (DUBs) are regulators of ubiquitin signaling. Here, we report on the presence of an additional DUB class broadly distributed in eukaryotes and several bacteria. The only described members of this family are the large tegument proteins of herpesviruses, which are attached to the outside of the viral capsid. By using a bioinformatics screen, we have identified distant homologs of this VTD (Viral tegument-like DUB) family in vertebrate transposons, fungi, insects, nematodes, cnidaria, protists and bacteria. While some VTD activities resemble viral tegument DUBs in that they favor K48-linked ubiquitin chains, other members are highly specific for K6- or K63-linked ubiquitin chains. The crystal structures of K48- and K6-specific members reveal considerable differences in ubiquitin recognition. The VTD family likely evolved from non-DUB proteases and spread through transposons, many of which became ‘domesticated’, giving rise to the Drosophila male sterile (3)76Ca gene and several nematode genes with male-specific expression.

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Mechanism of Lys6 poly-ubiquitin specificity by the L. pneumophila deubiquitinase LotA

Cited by 3 publications

References 80 publications

Structural insights into ubiquitin chain cleavage byLegionellaovarian tumor deubiquitinases

Structural insights into ubiquitin chain cleavage byLegionellaovarian tumor deubiquitinases

A new family of eukaryotic and bacterial deubiquitinases spreading and diversifying through transposons and horizontal gene transfer

A widely distributed family of eukaryotic and bacterial deubiquitinases related to herpesviral large tegument proteins

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