Huan-Xiang Zhou

Rate constants and mechanisms of intrin-sically disordered proteins binding to structured targets

PH 3024 (Seminarroom E22)

13.04.2018, 13:00


Amyloid Intrinsically disordered proteins (IDPs) play key roles in signaling and regulation. Many IDPs undergo folding upon binding to their targets. We have proposed that coupled folding and binding of IDPs generally follow a dock-and-coalesce mechanism, whereby a segment of the IDP, through diffusion, docks to its cognate subsite and, subsequently, the remaining segments coalesce around their subsites [1]. Parallel dock-and-coalesce pathways (initiated by different docking segments) may exist but one pathway may dominate [2]. By combining experiment and computation, we have determined the precise form of dock-and-coalesce operating in the association between the intrinsically disordered GTPase binding domain (GBD) of the Wiskott-Aldrich Syndrome protein (WASP) and the Cdc42 GTPase [3, 4]. In the major binding pathway, the N-terminal basic region (BR) has been identified as the docking segment whereas the middle CRIB motif and the C-terminal subdomain (Csub) as the coalescing segments. Recently we have designed mutations to alter binding pathways. By slowing down the BR docking rate and accelerating the Csub docking rate, these mutations are able to promote a minor binding pathway into the new major binding pathway. Together, these results demonstrate that the dock-and-coalesce mechanism provides a framework for quantitatively understanding the rate constants and mechanisms of IDP binding and it is now possible to design mutations that enable IDPs to follow specific binding pathways.