FAM105A/OTULINL Is a Pseudodeubiquitinase of the OTU-Class that Localizes to the ER Membrane.

Abstract

Pseudoenzymes have been identified across a diverse range of enzyme classes and fulfill important cellular functions. Examples of pseudoenzymes exist within ubiquitin conjugating and deubiquitinase (DUB) protein families. Here we characterize FAM105A/OTULINL, the only putative pseudodeubiquitinase of the ovarian tumor protease (OTU domain) family in humans. The crystal structure of FAM105A revealed that the OTU domain possesses structural deficiencies in both active site and substrate-binding infrastructure predicted to impair normal DUB function. We confirmed the absence of catalytic function against all ubiquitin linkages and an inability of FAM105A to bind ubiquitin compared with catalytically active FAM105B/OTULIN. FAM105A co-localized with KDEL markers and Lamin B1 at the endoplasmic reticulum (ER) and nuclear envelope, respectively. Accordingly, the FAM105A interactome exhibited significant enrichment in proteins localized to the ER/outer nuclear, Golgi and vesicular membranes. In light of undetectable deubiquitinase activity, we posit that FAM105A/OTULINL functions through its ability to mediate protein-protein interactions.

• Authors: Derek F Ceccarelli, Sofiia Ivantsiv, Amber Anne Mullin, Etienne Coyaud, Noah Manczyk, Pierre Maisonneuve, Igor Kurinov, Liang Zhao, Chris Go, Anne-Claude Gingras, Brian Raught, Sabine Cordes, Frank Sicheri
• Journal: Structure (London, England : 1993) (Structure) Vol. 27 Issue 6 Pg. 1000-1012.e6 (06 04 2019) ISSN: 1878-4186 [Electronic] United States
• PMID: 31056421 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Chemical References

• Ubiquitin
• Ubiquitin-Conjugating Enzymes
• Endopeptidases
• OTULIN protein, human
• Deubiquitinating Enzymes

Topics

• Amino Acid Sequence
• Animals
• Catalytic Domain
• Cell Line, Tumor
• Crystallography, X-Ray
• Deubiquitinating Enzymes (chemistry, genetics, metabolism)
• Endopeptidases (chemistry, genetics, metabolism)
• Endoplasmic Reticulum (metabolism)
• HEK293 Cells
• Humans
• Intracellular Membranes (metabolism)
• Mice
• Models, Molecular
• Protein Binding
• Protein Domains
• Sequence Homology, Amino Acid
• Ubiquitin (chemistry, metabolism)
• Ubiquitin-Conjugating Enzymes (chemistry, genetics, metabolism)