Exchange Factors

The ras superfamily of GTPases bind guanosine triphosphate and hydrolyse it to guanosine diphosphate. The rate of hydrolysis of GTP on p21^ras is greatly increased by GTPase-activating proteins such as GAP and NF-1 in mammalian cells (see Chapter 22) and IRA proteins in yeast (see Chapter 23). The intrinsic rate at which ras proteins will exchange bound nucleotide for nucleotide in solution is extremely slow in the presence of physiological levels of magnesium ions: ¹ the half-life for exchange of bound nucleotide is in the order of one hour. Without the intervention of some system for stimulating nucleotide exchange, ras proteins would be expected to be almost exclusively GDP-bound in the cell. Several lines of evidence indicate that the GTP-bound form of the protein is biologically active while the GDP-bound form is inactive (see Chapter 6). Without exchange factors, normal ras would therefore be continuously locked in the “off” state. A priori, it therefore, seems likely that exchange factors should exist for ras proteins in order to allow the accumulation of biologically effective levels of the active p21-GTP form. It should be noted that since more than 95% of the guanine nucleotide in the cytosol is GTP rather than GDP, ² the exchange of nucleotide need not necessarily be a directed replacement of GDP by GTP: the circumstances of p21^ras in the cell ensure that this will come about anyway.