Structural basis and specificity of human otubain 1-mediated deubiquitination.
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 sub...
| Hlavní autoři: | , , , , , , , , |
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| Médium: | Journal article |
| Jazyk: | English |
| Vydáno: |
2009
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| _version_ | 1826305841769218048 |
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| author | Edelmann, M Iphöfer, A Akutsu, M Altun, M di Gleria, K Kramer, H Fiebiger, E Dhe-Paganon, S Kessler, B |
| author_facet | Edelmann, M Iphöfer, A Akutsu, M Altun, M di Gleria, K Kramer, H Fiebiger, E Dhe-Paganon, S Kessler, B |
| author_sort | Edelmann, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T06:38:59Z |
| format | Journal article |
| id | oxford-uuid:f8a0961b-8876-450c-be0e-0fc8c20c337d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:38:59Z |
| publishDate | 2009 |
| record_format | dspace |
| spelling | oxford-uuid:f8a0961b-8876-450c-be0e-0fc8c20c337d2022-03-27T12:51:44ZStructural basis and specificity of human otubain 1-mediated deubiquitination.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:f8a0961b-8876-450c-be0e-0fc8c20c337dEnglishSymplectic Elements at Oxford2009Edelmann, MIphöfer, AAkutsu, MAltun, Mdi Gleria, KKramer, HFiebiger, EDhe-Paganon, SKessler, BOTUB (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. |
| spellingShingle | Edelmann, M Iphöfer, A Akutsu, M Altun, M di Gleria, K Kramer, H Fiebiger, E Dhe-Paganon, S Kessler, B Structural basis and specificity of human otubain 1-mediated deubiquitination. |
| title | Structural basis and specificity of human otubain 1-mediated deubiquitination. |
| title_full | Structural basis and specificity of human otubain 1-mediated deubiquitination. |
| title_fullStr | Structural basis and specificity of human otubain 1-mediated deubiquitination. |
| title_full_unstemmed | Structural basis and specificity of human otubain 1-mediated deubiquitination. |
| title_short | Structural basis and specificity of human otubain 1-mediated deubiquitination. |
| title_sort | structural basis and specificity of human otubain 1 mediated deubiquitination |
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