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<StructureSection load='1nvu' size='500' side='right' caption='Human RAS P21 dimer (green and blue) complex with son of sevenless protein homolog 1 (olive), GTP (stick model) , phosphate and Mg+2 (green) ions [[1nvu]]'>
<StructureSection load='' 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' >
[[Image:Hras.png|200px|left|]]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;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 [[H-RasK117R mutant]] and [[User:Joseph Lipsick/RAS]].
[[Image:Hras.png|200px|left|]]&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;
 
 
 
 
 


&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The two most common oncogenic mutations in ''H-RAS'' affect residues <scene name='User:Joseph_Lipsick/RAS/Ras-gtp_gly12/1'>Gly12 </scene> and <scene name='User:Joseph_Lipsick/RAS/Ras-gtp_gln61/1'>Gln61</scene>, both of which are adjacent to the bound GTP molecule.  These oncogenic mutations greatly inhibit the intrinsic GTPase activity, thereby causing the RAS switch to spend more time in the "ON" position. The RAS proteins are present at the plasma membrane and transmit signals from transmembrance receptor tyrosine kinases (e.g. EGF and PDGF receptors) to downstream intracellular effectors that include the MAPK protein kinase cascade and the [[PI3K|PI3K lipid kinase]].  Binding of EGF or PDGF to their receptors causes a relocalization of a '''G'''uanine Nucleotide '''E'''xchange '''F'''actor (GEF) protein to the plasma membrane.  The structure of <scene name='User:Joseph_Lipsick/RAS/Ras-sos/5'>SOS</scene>, a prototypic GEF, together with RAS implies that the GEF prys open the nucleotide binding site with a loss of bound GDP.  The ten-fold higher ratio of GTP to GDP within the cell results in the replacement of RAS-GDP ("OFF" state) with RAS-GTP ("ON" state). Consistent with this model, gain-of-function mutations of ''GEF'' genes can be oncogenic (e.g. ''VAV'' oncogene) even in the absence of mutations of ''RAS''.  Conversely, a GTPase Activating Protein (<scene name='User:Joseph_Lipsick/RAS/Ras-gap/5'>GAP</scene>) can bind to RAS-GTP and increase the rate of the intrinsic RAS GTPase.  Consistent with this model, loss-of-function mutations of GAP genes (e.g. NF1 tumor suppressor) can be oncogenic even in the absence of mutations of ''RAS'' itself.  More details in [[Allosteric modulation of H-Ras GTPase]].
</StructureSection>


==3D structures of GTPase Hras==


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}


[[5p21]], [[221p]], [[1ioz]], [[1p2t]], [[3k8y]], [[3l8z]], [[3rry]], [[3tgp]], [[3lbh]], [[4dlr]], [[4dls]], [[4dlt]], [[4dlu]], [[4dlv]], [[4dlw]], [[4dlx]], [[4dly]], [[4dlz]] - hHRAS catalytic domain – human<BR / >
[[1plj]], [[1plk]], [[1pll]] – hHRAS catalytic domain - Laue<BR / >
[[221p]], [[421p]], [[521p]], [[621p]], [[721p]], [[821p]], [[1agp]], [[3i3s]], [[3k9n]], [[3lo5]], [[3k9l]], [[3oiu]], [[3oiv]], [[3oiw]] – hHRAS catalytic domain (mutant)<br />
[[3v4f]] – HRAS - rat


===HRAS p21 complex with nucleotides===


[[1crp]], [[1crq]], [[1crr]], [[1aa9]] – hHRAS catalytic domain + GDP - NMR<BR / >
[[1q21]], [[4q21]] – hHRAS catalytic domain + GDP<BR / >
[[4l9s]] - hHRAS catalytic domain (mutant) + GDP<br />
[[4l9w]] - hHRAS catalytic domain (mutant) + GMPPNP<br />
[[6q21]], [[121p]] – hHRAS catalytic domain + GCP<BR / >
[[1qra]] - hHRAS catalytic domain + GTP<BR / >
[[1ctq]], [[4efl]] - hHRAS catalytic domain + GPPNHP<BR / >
[[1xcm]], [[2cl0]], [[2rga]], [[2rgb]], [[2rgc]], [[2rgd]], [[2rge]], [[2rgg]], [[3kkm]], [[3kkn]], [[4efm]], [[4efn]] - hHRAS catalytic domain (mutant) + GPPNHP<BR / >
[[1gnp]], [[1gnq]] - hHRAS catalytic domain + guanylate derivative<br / >
[[2lcf]] - hHRAS catalytic domain (mutant) + guanylate derivative - NMR<BR / >
[[1p2s]], [[1p2u]], [[1p2v]], [[3rrz]], [[3rs0]], [[3rs2]], [[3rs4]], [[3rs7]], [[3rsl]], [[3rso]] - hHRAS catalytic domain + alcohol + guanylate derivative<br / >
[[3rs3]], [[3rs5]] - hHRAS catalytic domain + small organic molecule + guanylate derivative<br / >
[[3lbh]], [[3lbi]], [[3lbn]] - hHRAS catalytic domain + salt + guanylate derivative<br / >
[[3l8y]] - hHRAS catalytic domain + cyclen + guanylate derivative<br / >
[[1clu]], [[1rvd]], [[1iaq]], [[1gnr]] - hHRAS catalytic domain (mutant) + GTP derivative<br / >
[[1lf0]], [[1zw6]], [[2cl6]], [[2cl7]], [[2clc]], [[2evw]], [[1jah]], [[1jai]]- hHRAS catalytic domain (mutant) + GTP<BR / >
[[1lf5]], [[1xj0]], [[1zvq]], [[2cld]], [[2ce2]], [[2quz]], [[2x1v]], [[2q21]] - hHRAS catalytic domain (mutant) + GDP<BR / >


===HRAS p21 complex with protein===


[[1wq1]] - hHRAS catalytic domain + p120GAP catalytic domain<BR / >
[[1bkd]], [[1nvw]] - hHRAS catalytic domain + son of sevenless-1<BR / >
[[1nvu]], [[1nvv]], [[1nvx]], [[1xd2]], [[4nyi]], [[4nyj]], [[4nym]] - hHRAS catalytic domain (mutant) + son of sevenless-1 homolog<BR / >
[[1k8r]] - hHRAS catalytic domain + Byr2 RAS-binding domain<BR / >
[[2c5l]] - hHRAS catalytic domain (mutant) + phosphoinositide-specific phospholipase RA2 domain<BR / >
[[2uzi]], [[2vh5]] - hHRAS catalytic domain (mutant) + antibody<BR / >
[[3ddc]] - hHRAS catalytic domain (mutant) + Ras association domain containing family protein RAS-binding domain<BR / >
[[3kud]], [[4g0n]], [[4g3x]] - hHRAS catalytic domain + RAF proto-oncogene Ser/Thr-protein kinase<br />
[[1lfd]] - hHRAS catalytic domain + Ral guanine nucleotide dissociation stimulator RAS-binding domain<br />
[[4k81]] – hHRAS + growth factor receptor-bound protein<br />


[[2lwi]] – hHRAS + inhibitor<br />
__TOC__
== Function ==
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]).<br />  For additional details on RAS see<br />
[[H-RasK117R mutant]]<br />
[[Ras Protein and Pancreas Cancer]]<br />
[[User:Joseph Lipsick/RAS]]<br />
[[H RAS protein (hebrew)]]<br />
[[Chani elisha]].


== Disease ==
&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;The two most common oncogenic mutations in ''H-RAS'' affect residues <scene name='User:Joseph_Lipsick/RAS/Ras-gtp_gly12/1'>Gly12 </scene> and <scene name='User:Joseph_Lipsick/RAS/Ras-gtp_gln61/1'>Gln61</scene>, both of which are adjacent to the bound GTP molecule.  These oncogenic mutations greatly inhibit the intrinsic GTPase activity, thereby causing the RAS switch to spend more time in the "ON" position. The RAS proteins are present at the plasma membrane and transmit signals from transmembrance receptor tyrosine kinases (e.g. EGF and PDGF receptors) to downstream intracellular effectors that include the MAPK protein kinase cascade and the [[PI3K|PI3K lipid kinase]].  Binding of EGF or PDGF to their receptors causes a relocalization of a '''G'''uanine Nucleotide '''E'''xchange '''F'''actor (GEF) protein to the plasma membrane.  The structure of <scene name='User:Joseph_Lipsick/RAS/Ras-sos/5'>SOS</scene>, a prototypic GEF, together with RAS implies that the GEF prys open the nucleotide binding site with a loss of bound GDP.  The ten-fold higher ratio of GTP to GDP within the cell results in the replacement of RAS-GDP ("OFF" state) with RAS-GTP ("ON" state). Consistent with this model, gain-of-function mutations of ''GEF'' genes can be oncogenic (e.g. ''VAV'' oncogene) even in the absence of mutations of ''RAS''.  Conversely, a GTPase Activating Protein (<scene name='User:Joseph_Lipsick/RAS/Ras-gap/5'>GAP</scene>) can bind to RAS-GTP and increase the rate of the intrinsic RAS GTPase.  Consistent with this model, loss-of-function mutations of GAP genes (e.g. NF1 tumor suppressor) can be oncogenic even in the absence of mutations of ''RAS'' itself.  More details in<br />
[[Allosteric modulation of H-Ras GTPase]]<br />
[[Proteins involved in cancer]].


== Structural highlights ==
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. <scene name='37/379455/Cv/7'>Mg coordination site</scene>.
==3D structures of GTPase Hras==
[[GTPase Hras 3D structures]]
</StructureSection>


==References==
==References==
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* Bos, Rehmann, and Wittinghofer. Cell. 2007. 129: 865-77.  
* Bos, Rehmann, and Wittinghofer. Cell. 2007. 129: 865-77.  
* Karnoub and Weinberg. Nature Rev Mol Cell Biol. 2008. 9: 517-531.
* Karnoub and Weinberg. Nature Rev Mol Cell Biol. 2008. 9: 517-531.
 
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

Joseph Lipsick, David Canner, Michal Harel, Alexander Berchansky, Jaime Prilusky, Joel L. Sussman
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