GTPase and ATPase tangos during intracellular protein targeting

Abstract

Rougly one third of the proteome are destined for the cellular membrane, whose proper localization is essential for the structure and function of all cells. The signal recognition particle (SRP) is a universally conserved cellular machinery that couples the synthesis of membrane and secretory proteins to their proper cellular localization, and has served as a paradigm to understand the molecular basis of protein localization. Using a combination of chemical, biophysical, structural and cellular approaches, our work has established a quantitative framework for how two highly homologous GTPases in the SRP and SRP receptor use a novel GTPase cycle to drive this fundamental cellular pathway, and elucidated how fidelity of protein localization by the SRP is achieved through a combination of binding, induced fit, and kinetic proofreading mechanisms. These findings also define a novel class of 'dimerization-activated' GTPases, represented by the SRP and SRP receptor, whose regulatory principles may extend to a growing number of nucleotide hydrolases that drive diverse cellular processes.

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