Structural basis for the human SENP5’s SUMO isoform discrimination
Nature Communications, vol. 16, pp. 4764
Abstract
Post-translational SUMO modification is a widespread mechanism for regulating protein function within cells. In humans, SUMO-conjugated proteins are partially regulated by the deconjugating activity of six SENP family members. The proteolytic activity of these enzymes resides within a conserved catalytic domain that exhibits specificity for the two primary SUMO isoforms: SUMO1 and SUMO2/3. SENP5, along with SENP3, are nucleolar proteins involved in ribosome biogenesis and preferentially target SUMO2/3 isoforms. Here, we present the crystal structures of human SENP5 in complex with both SUMO1 and SUMO2 isoforms. These structures reveal a minimal complex interface and elucidate the molecular basis for SENP5’s preference for the SUMO2 isoform. This preference can be attributed to a basic patch surrounding SENP5 Arg624 at the interface. Swapping mutagenesis and structural analysis demonstrate that Arg624 is favorably oriented to interact with Asp63 in SUMO2/3, while its interaction with the equivalent Glu67 in SUMO1 is less favorable. These results suggest that subtle structural differences within SUMO isoforms can significantly influence their deconjugation by SENP enzymes, opening new avenues for exploring the regulation of SUMOylation in various cellular processes and for developing therapeutic agents targeting SUMOylation pathways. SUMO modification regulates protein function, with SENP enzymes controlling SUMO removal. Here, the authors present crystal structures of SENP5 bound to SUMO1 and SUMO2, revealing how structural features drive its preference for SUMO2 and offering insights into SUMOylation regulation.
Authors 10
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Universitat Autònoma de Barcelona
Affiliation as printed
Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
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Qingdao University · Universitat Autònoma de Barcelona
Affiliation as printed
Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
Qingdao University, Qingdao, China
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
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Consorci Institut D'Investigacions Biomediques August Pi I Sunyer
Affiliation as printed
Institut de Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBABS), Barcelona, Spain
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Universitat Autònoma de Barcelona
Affiliation as printed
Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
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Universitat Autònoma de Barcelona
Affiliation as printed
Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
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Universitat Autònoma de Barcelona
Affiliation as printed
Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain
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Consorci Institut D'Investigacions Biomediques August Pi I Sunyer
Affiliation as printed
Institut de Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBABS), Barcelona, Spain
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Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology, Leiden University Medical Center (LUMC), Leiden, The Netherlands
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David Reverter corresponding
Universitat Autònoma de Barcelona
Affiliation as printed
Institut de Biotecnologia i de Biomedicina (IBB) and Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. david.reverter@uab.cat
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