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Abstract:
The activity of Rho GTPases, responsible for a wide range of events determining cell morphology, is orchestrated by guanine nucleotide dissociation inhibitors (RhoGDIs), together forming an intensely researched family of regulatory proteins. Their function has been assumed to be based on steric hindrance of nucleotide exchange by their N-terminus, whose structural properties have, however, remained contradictory. Here we show that this crucial functional element of the inhibitor contains well-defined temporary structural features that increase binding affinity to the client but at the same time maintain a very high degree of plasticity, of benefit for the multi-step recruitment (excavation) of the client from its membrane-bound state. On the basis of the multitude of MD-, NMR- (chemical shifts, relaxation, RDCs, 3J couplings, and NOEs) and FRET-based dynamics data obtained, its sterically exerted inhibitory action previously assumed, by contrast, now seems highly unlikely. Apart from its importance for molecular regulation of cell morphological events and pharmacological avenues for the Rho family in particular, the study demonstrates the versatility of the enormous spectrum of different degrees of a co-existence of order and disorder that is associated with different kinds of protein interactions.
