A New and Un-Conventional Ultrafast Binding Mechanism of Intrinsically Disordered Proteins to Structured Partners

Abstract

Intrinsically disordered proteins (IDPs) mediate several and very diverse processes such as signaling, regulation and formation of entropic barriers. Such functions often involve the binding between an IDP and one or more structured partners. Several mechanisms to describe the binding of IDPs to structured proteins have been identified: the conformational selection model implies that, along the conformational ensemble explored by the IDP, binding-prone configurations are abundant and favor binding. In contrast, the induced-fit model describes binding as a series of conformational changes of the IDP that can form secondary structure elements upon binding. By investigating the association between the intrinsically disordered nucleoporin Nup153 and its structured binding partner Importin-β through means of single-molecule FRET experiments, molecular dynamics (MD) and Brownian dynamics (BD) simulations, we have identified a new mechanism that leads to the formation of complexes without the need of any structural re-arrangement or selection of a pre-configured conformation of the IDP. We found that binding can occur between Importin-β and highly diverse configurations of Nup153 in a globular-like state. Being conformational-independent, the association is solely regulated by the availability of nucleoporin's Phe-Gly dipeptide responsible for the interaction with Importin. More importantly, since conformational adaptations are absent, specific binding is rapid enough to be observed on the sub-microsecond time scale of the MD simulations. This ultrafast binding mechanism of nucleoporin to Importin-β can justify the observation of rapid, yet selective nucleo-cytoplasmatic transport. Our joint computational and experimental approach could help to explain if a similar binding scenario also applies to other repetitive IDPs.