GTPase HRas: Difference between revisions

<StructureSection load='4l9s' size='350' side='right' caption='Human RAS P21 catalytic subunit complex with GDP, Ca+2 (large green), K+ (purple) and Mg+2 ion (small green) [[4l9s]]' scene='37/379455/Cv/1' >

The ''RAS'' gene family was discovered due to the presence of two closely related retroviral cancer genes (oncogenes) within the Harvey and Kirsten '''RA'''t '''S'''arcoma viruses.  These retroviral oncogenes arose via capture of two normal cellular genes, ''H-RAS'' and ''K-RAS''.  A [[DNA]] transfection assay for [[Oncogenes|oncogenes]] in human bladder cancer later identified the same ''H-RAS'' gene. Remarkably, the mutated oncogenic form of ''H-RAS'' differed from its normal counterpart by a single nucleotide change that caused a single amino acid substitution.  Biochemical studies of purified RAS proteins revealed that they were capable of binding nucleotides, with a particularly high affinity for GTP. Extensive genetic, biochemical, and structural studies have established a model in which the RAS proteins function as molecular switches, as do related GTP-binding proteins.  The RAS switch is "ON" when it binds <scene name='User:Joseph_Lipsick/RAS/Ras-gtp_switches/5'>GTP</scene>, and is "OFF" when it binds <scene name='User:Joseph_Lipsick/RAS/Ras-gdp_switches/11'>GDP</scene>. The changes in protein conformation between the <scene name='User:Joseph_Lipsick/RAS/Ras-gtp_switch_i_ii_spacefill/2'>"ON"</scene> and <scene name='User:Joseph_Lipsick/RAS/Ras-gdp_switch_i_ii_spacefill/3'>"OFF"</scene> states are not very large.  These changes primarily occur in two regions known as SWITCH I (yellow) and SWITCH II (magenta), and can be visualized by toggling the spin off and on in these partial space-filling models.  The RAS protein itself has an intrinsic GTPase activity, thereby limiting the duration of time spent in the "ON" configuration.  The binding sites of the nucleotide and the magnesium ion are revealed in high detail and consists of a characteristic <scene name='5p21/Ligand_binding_site/1'>Walker motif</scene> (GXXXXGK[T/S]).  For additional details see<br />

Interactions with the <scene name='37/379455/Cv/6'>nucleotide phosphate moiety in the active site</scene> of GTPase Hras determine its active conformation<ref>PMID:242356730</ref>. Water molecules shown as red spheres.