title: Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism.
abstract: Small ubiquitin-related modifiers (SUMOs) are conjugated to proteins to regulate a variety of cellular processes. SENPs are cysteine proteases with a catalytic center located within a channel between two subdomains that catalyzes SUMO C-terminal cleavage for processing of SUMO precursors and de-SUMOylation of target proteins. The β-grasp domain of SUMOs binds to an exosite cleft, and allosterically activates SENPs via an unknown mechanism. Our molecular dynamics simulations showed that binding of the β-grasp domain induces significant conformational and dynamic changes in SENP1, including widening of the exosite cleft and quenching of nanosecond dynamics in all but a distal region. A dock-and-coalesce mechanism emerges for SENP-catalyzed SUMO cleavage: the wedging of the β-grasp domain enables the docking of the proximal portion of the C-terminus and the strengthened cross-channel motional coupling initiates inter-subdomain correlated motions to allow for the distal portion to coalesce around the catalytic center.
authors: Henan Engineering Research Center of Chiral Hydroxyl Pharmaceuticals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, China.
authors: Jingjing
authors: J
authors: Guo
authors: Department of Physics, Institute of Molecular Biophysics, Florida State University, Tallahassee, United States.
authors: Huan-Xiang
authors: 0000-0001-9020-0302
authors: HX
authors: Zhou
mesh_terms: D000494:Allosteric Regulation; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D025842:SUMO-1 Protein / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases
keywords: SUMOylation; allosteric activation; biophysics; dock-and-coalesce; human; protein dynamics; structural biology