w DEI VVEEN LELLS ANU THEIR ENVIKUNMEN Protein ADP kinase 1 ATP Protein kinase 2 Inactive Protein phosphatase 1 Active ADP ATP Pr rotein kinase 3 Active Protein phosphatase 2 Inactive ADP P Active Protein phosphatase 3 protein Inactive protein substrate substrate (e. g,, transcription factor) P DNA Response
(2) Switch proteins--G protein 1. The first group of G-proteins comprises the superfamily of Gs, G;, Go, G, and the transducin families bourne 1986, Stryer 1986 These proteins are heterotrimeric and are important for signal transduction from mem brane receptors with seven transmembrane domains to various effectors such as adenylate cyclase and cyclic GMP-phosphodiesterase. Typically, the heterotrimeric G-proteins consist of a, B, and y subunits. This class of G-pro- teins is reviewed elsewhere in this book 2. The second group is the monomeric low or small molecular weight G-proteins(LMWG)with molecular masses ranging from 18 to 32 kDaIn this review we will focus on LMWG-proteins, a rapidly growing family of proteins represented by the ras oncogene as the prototype
(2) Switch proteins-- G protein
General structure LMWG-proteins of molecular weight 18-32 kDa include ras-related pro teins and many oncogene products(Barbacid 1987, Burgoyne 1989, Santos and Nebreda 1989). These proteins regulate various aspects of cell growth and differentiation, gene expression, cytoskeletal assembly and cell motility protein and lipid trafficking, nuclear transport, and host defense(Hall 1992 Nuoffer and Balch 1994, Bokoch 1995, Lowy and Willumsen 1993, and Marshall 1995). They lack a site for ADP ribosylation with either pertussis or cholera toxins, although some of them can be ADP-ribosylated with botulinum toxins(Quilliam et al 1989, Nobes and Hall 1995) LMWG proteins comprise more than 50 members, and can be catego- rized into several subfamilies such as Ras, Ral, Rab, Rho, Rac, etc. ( Capon et al 1983, Schmidt et al 1986, Yamamoto et al 1988). A more simplified and general classification of these proteins, however, is based on sequence ho mology to Ras, and includes four groups, namely(1) Ras/Rap/Ral, (2) Rhol/Rac, (3)Ypt/Rab, and(4) Arf. These proteins share 20-50% overall homology to ras, and in addition have several common features, including four conserved domains, as shown in Figure 3-1 In this simplified model of small molecular weight G-proteins, the open boxes represent conserved sequence motifs that are necessary for guanine
Putative effector Variable domain D omaIr (Residues 165-185) (Residues 32-40) NH2-terminal COoH-terminal Figure 3-1. Common features of small molecular weight G-proteins
protein cycle and their regulation GEF Switch GEFGTP ON(GEF G protein accessory proteins Inactive Active G protein o G protein -GDP GTP SDI: GDP dissociation proteins, GDP Inactive G[ DP CGDI o G protein GEF: GDP/GTP exchange factor AGDI GEF Inactive Inactive GAP: GTPase activating protein G protein Active G target otein protein GAP GTP Active GDP target Clock protein Switch Inactive OFF g target protein transmitted downstream ()
G protein accessory proteins: SDI: GDP dissociation proteins; GEF: GDP/GTP exchange factor; GAP: GTPase activating protein G protein cycle and their regulation