Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SUMOylation, one of the most important protein post-translational modifications, plays critical roles in a variety of physiological and pathological processes. SENP (Sentrin/SUMO-specific protease), a family of SUMO-specific proteases, is responsible for the processing of pre-SUMO and removal of SUMO from conjugated substrates. SUMO4, the latest discovered member in the SUMO family, has been found as a type 1 diabetes susceptibility gene and its maturation is not understood so far. Despite the 14 amino acid differences between pre-SUMO4 and SUMO2, pre-SUMO4 is not processed by SENP2 but pre-SUMO2 does. A novel interdisciplinary approach involving computational modeling and a FRET-based protease assay was taken to engineer pre-SUMO4 as a substrate of SENP2. Given the difference in net charge between pre-SUMO4 and pre-SUMO2, the computational framework analysis of electrostatic similarities of proteins was applied to determine the contribution of each ionizable amino acid in a model of SENP2-(pre-SUMO4) binding, and to propose pre-SUMO4 mutations. The specificities of the SENP2 toward different pre-SUMO4 mutants were determined using a quantitative FRET assay by characterizing the catalytic efficiencies (kcat/KM). A single amino acid mutation made pre-SUMO4 amenable to SENP2 processing and a combination of two amino acid mutations made it highly accessible as SENP2 substrate. The combination of the two approaches provides a powerful protein engineering tool for future SUMOylation studies.
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PMID:Engineering pre-SUMO4 as efficient substrate of SENP2. 2467 12