How does the switch II region of G‐domains work?

Abstract

The transition of guanine nucleotide binding proteins between the ‘on’ (GTP‐bound) and ‘off’ (GDP‐bound) states has become a paradigm of molecular switching after a chemical reaction. The mechanism by which the switch signal is transmitted to the downstream recipients in the intracellular signal pathway has been extensively studied by biochemical, biophysical and genetic methods, but a clear picture of this process has yet to emerge. Based on the similarities of ras‐p21 and elongation factor Tu we propose here a model of the GDP state of ras‐p21 that is in agreement with all relevant experimental evidence. The model provides important clues about: (1) a possible molecular mechanism for signal transmission from the site of GTP hydrolysis to downstream effectors; (2) a major conformational change during signal generation and a key residue involved in this process (Tyr‐64); and (3) regions in ras‐p21 that can be differentially recognized by binding to external partners in a GTP/GDP state dependent fashion, most notably residues D69, Q70, R73, T74, R102, K104, D105 at the end of the α‐helices 2 and 3.