Journal Article

Structural Insights into the Regulation Mechanism of Small GTPases by GEFs

Shimizu, Toshiyuki, Toma-Fukai, Sachiko

2019

Overview

Small GTPases are key regulators of cellular events, and their dysfunction causes many types of cancer. They serve as molecular switches by cycling between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound states. GTPases are deactivated by GTPase-activating proteins (GAPs) and are activated by guanine-nucleotide exchange factors (GEFs). The intrinsic GTP hydrolysis activity of small GTPases is generally low and is accelerated by GAPs. GEFs promote GDP dissociation from small GTPases to allow for GTP binding, which results in a conformational change of two highly flexible segments, called switch I and switch II, that enables binding of the gamma phosphate and allows small GTPases to interact with downstream effectors. For several decades, crystal structures of many GEFs and GAPs have been reported and have shown tremendous structural diversity. In this review, we focus on the latest structural studies of GEFs. Detailed pictures of the variety of GEF mechanisms at atomic resolution can provide insights into new approaches for drug discovery.

• Publisher: MDPI AG,MDPI
• Subject: Amino acids / Animals / Binding sites / crystal structure / Enzyme Activation / Feedback, Physiological / GEF / Guanine Nucleotide Exchange Factors - chemistry / Guanine Nucleotide Exchange Factors - metabolism / Humans / local protein unfolding / Monomeric GTP-Binding Proteins - chemistry / Monomeric GTP-Binding Proteins - metabolism / Phylogeny / Protein Folding / Proteins / regulation mechanism / Review / small GTPases