Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism

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 b-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 b-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 SENPcatalyzed SUMO cleavage: the wedging of the b-grasp domain enables the docking of the proximal portion of the C-terminus and the strengthened cross-channel motional coupling initiates intersubdomain correlated motions to allow for the distal portion to coalesce around the catalytic center.