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PMID:18954305

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Citation

Edelmann, MJ, Iphöfer, A, Akutsu, M, Altun, M, di Gleria, K, Kramer, HB, Fiebiger, E, Dhe-Paganon, S and Kessler, BM (2009) Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem. J. 418:379-90

Abstract

OTUB (otubain) 1 is a human deubiquitinating enzyme that is implicated in mediating lymphocyte antigen responsiveness, but whose molecular function is generally not well defined. A structural analysis of OTUB1 shows differences in accessibility to the active site and in surface properties of the substrate-binding regions when compared with its close homologue, OTUB2, suggesting variations in regulatory mechanisms and substrate specificity. Biochemical analysis reveals that OTUB1 has a preference for cleaving Lys(48)-linked polyubiquitin chains over Lys(63)-linked polyubiquitin chains, and it is capable of cleaving NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8), but not SUMO (small ubiquitin-related modifier) 1/2/3 and ISG15 (interferon-stimulated gene 15) conjugates. A functional comparison of OTUB1 and OTUB2 indicated a differential reactivity towards ubiquitin-based active-site probes carrying a vinyl methyl ester, a 2-chloroethyl or a 2-bromoethyl group at the C-terminus. Mutational analysis suggested that a narrow P1' site, as observed in OTUB1, correlates with its ability to preferentially cleave Lys(48)-linked ubiquitin chains. Analysis of cellular interaction partners of OTUB1 by co-immunoprecipitation and MS/MS (tandem mass spectrometry) experiments demonstrated that FUS [fusion involved in t(12;6) in malignant liposarcoma; also known as TLS (translocation in liposarcoma) or CHOP (CCAAT/enhancer-binding protein homologous protein)] and RACK1 [receptor for activated kinase 1; also known as GNB2L1 (guanine-nucleotide-binding protein beta polypeptide 2-like 1)] are part of OTUB1-containing complexes, pointing towards a molecular function of this deubiquitinating enzyme in RNA processing and cell adhesion/morphology.

Links

PubMed Online version:10.1042/BJ20081318

Keywords

Cells, Cultured; Cysteine Endopeptidases/chemistry; Cysteine Endopeptidases/metabolism; Cysteine Endopeptidases/physiology; Endopeptidases/chemistry; Endopeptidases/metabolism; Endopeptidases/physiology; Humans; Models, Biological; Models, Molecular; Protein Binding; Protein Conformation; Protein Processing, Post-Translational; Sequence Homology, Amino Acid; Structure-Activity Relationship; Substrate Specificity; Thiolester Hydrolases/chemistry; Ubiquitins/metabolism; Yeasts/enzymology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FUS

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96FW1

F

Seeded From UniProt

complete

HUMAN:RACK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96FW1

F

Seeded From UniProt

complete

HUMAN:OTUB2

enables

GO:0004843: thiol-dependent deubiquitinase

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:OTUB2

involved_in

GO:0071108: protein K48-linked deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:OTUB2

involved_in

GO:0070536: protein K63-linked deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:OTUB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P63244

F

Seeded From UniProt

complete

HUMAN:OTUB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35637

F

Seeded From UniProt

complete

HUMAN:OTUB1

enables

GO:0019784: NEDD8-specific protease activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:OTUB1

enables

GO:0004843: thiol-dependent deubiquitinase

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:OTUB1

involved_in

GO:0071108: protein K48-linked deubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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