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

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

  • Structure. 2019 Jun 4;27(6):1000-1012.e6. doi: 10.1016/j.str.2019.03.022.
Derek F Ceccarelli 1,  Sofiia Ivantsiv 2,  Amber Anne Mullin 2,  Etienne Coyaud 3,  Noah Manczyk 4,  Pierre Maisonneuve 1,  Igor Kurinov 5,  Liang Zhao 1,  Chris Go 2,  Anne-Claude Gingras 2,  Brian Raught 6,  Sabine Cordes 7,  Frank Sicheri 8
Affiliations

Affiliations

  • 1 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • 2 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 3 Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
  • 4 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 5 Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Argonne, IL 60439, USA.
  • 6 Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada. Electronic address: [email protected].
  • 7 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
  • 8 Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
PMID: 31056421 DOI: 10.1016/j.str.2019.03.022
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.

Keywords

BioID interactome; FAM105A; OTU domain; crystal structure; deubiquitinase; pseudoenzyme; subcellular localization; ubiquitin.

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