Sandbox 173: Difference between revisions

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===G Protein-Coupled Receptors===

Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of ~~signalling~~ and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref name="Article20">PMID:15251227</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref name="Article12"/>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref name="Article20"/>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case [http://en.wikipedia.org/wiki/Transducin transducin], which interacts with the cytoplasmic loops of the receptor<ref name="Article10">PMID:11698103</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref name="Article20"/>.

Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signaling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref name="Article20">PMID:15251227</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref name="Article12"/>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref name="Article20"/>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case [http://en.wikipedia.org/wiki/Transducin transducin], which interacts with the cytoplasmic loops of the receptor<ref name="Article10">PMID:11698103</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref name="Article20"/>.

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====Signalling Cascade and Polarization of the Cell Membrane====

The excited rhodopsin interacts with a large number of transducin molecules, found in the ~~cytoplasic~~ face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref name="Article6"/>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates [http://en.wikipedia.org/wiki/CGMP-specific_phosphodiesterase_type_5 cGMP-specific phosphodiesterase] by binding and removing its inhibitory subunit<ref name="Textbook">Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.</ref>.

The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasmic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref name="Article6"/>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates [http://en.wikipedia.org/wiki/CGMP-specific_phosphodiesterase_type_5 cGMP-specific phosphodiesterase] by binding and removing its inhibitory subunit<ref name="Textbook">Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.</ref>.

The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity. The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP<ref name="Textbook"/>. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve<ref name="Article6"/>.

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===Topology Overview===

The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref name="ArticleOpsin2">PMID:18563085</ref>. Also, in ~~constrast~~ to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref name="ArticleOpsin2"/>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref name="ArticleOpsin2"/>.

The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref name="ArticleOpsin2">PMID:18563085</ref>. Also, in contrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref name="ArticleOpsin2"/>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref name="ArticleOpsin2"/>.

===Activity===

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@@ Line 5: / Line 5: @@
 ===G Protein-Coupled Receptors===
-Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signalling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref name="Article20">PMID:15251227</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref name="Article12"/>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref name="Article20"/>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case [http://en.wikipedia.org/wiki/Transducin transducin], which interacts with the cytoplasmic loops of the receptor<ref name="Article10">PMID:11698103</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref name="Article20"/>.
+Rhodopsin is a member of the superfamily of G protein-coupled receptors that incorporate the activation of G proteins in their modulation of signaling and intracellular actions. Rhodopsin shares similar membrane topology with the members of the superfamily (Family A of the G protein-coupled receptors) which include the seven transmembrane helices, an extracellular N terminus and cytoplasmic C terminus<ref name="Article20">PMID:15251227</ref>. The seven-helical pattern is found from archaebacteria (specifically studied is bacteriorhodopsin) to humans, both which share the same retinylidene chromophore as well <ref name="Article12"/>. As the crystal structure for any G protein-coupled receptor with the seven transmembrane domain has only been solved for rhodopsin, rhodopsin may act as a reference for the structure and function relationship for other G protein-coupled receptors<ref name="Article20"/>. Like most G protein-coupled receptors, the activated rhodopsin catalyzes uptake of GTP by the heterotrimeric G protein, in this case [http://en.wikipedia.org/wiki/Transducin transducin], which interacts with the cytoplasmic loops of the receptor<ref name="Article10">PMID:11698103</ref>. However, the covalent binding nature of rhodopsin to its retinal ligand is unlike most G protein-coupled receptors. As well, another difference of rhodopsin from the members of this superfamily relates to light as the inducer for activation<ref name="Article20"/>.
@@ Line 55: / Line 55: @@
 <applet load='1u19' size='300' color='black' frame='true' align='right' caption='Phosphorylation of Rhodospin. The generated structure is from Chain A.'/>
 ====Signalling Cascade and Polarization of the Cell Membrane====
-The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref name="Article6"/>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates [http://en.wikipedia.org/wiki/CGMP-specific_phosphodiesterase_type_5 cGMP-specific phosphodiesterase] by binding and removing its inhibitory subunit<ref name="Textbook">Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.</ref>.
+The excited rhodopsin interacts with a large number of transducin molecules, found in the cytoplasmic face of the disk membrane. Transducin is a member of the heterotrimeric GTP-binding proteins family, and it binds to GDP in the dark. This interaction generates a signaling cascade where transducin molecules are activated through the trigger of GDP-GTP nucleotide exchange in the α subunit<ref name="Article6"/>. Each activated transducin dissociates into Tα-GTP and Tβγ subunits, and Tα-GTP activates [http://en.wikipedia.org/wiki/CGMP-specific_phosphodiesterase_type_5 cGMP-specific phosphodiesterase] by binding and removing its inhibitory subunit<ref name="Textbook">Nelson, D., and Cox, M. Lehninger Principles of Biochemistry. 2008. 5th edition. W. H. Freeman and Company, New York, New York, USA. pp. 462-465.</ref>.
 The cGMP phosphodiesterase is an integral protein of the retina with its active site on the cytoplasmic side of the disk. Its inhibitory subunit tightly binds to it in the dark and suppresses its activity.  The now activated phosphodiesterase degrades many molecules of cGMP, efficiently decreasing the concentration of cGMP<ref name="Textbook"/>. This results in the closing of the cGMP-gated cation channels in the plasma membrane of the outer segment. The cell hyperpolarizes due to the decrease in the influx of sodium and calcium ions, which results in the decrease of the release of glutamate into the synaptic cleft. This electric signal of this hyperpolarization is sent to the brain through ranks of interconnecting neurons and then through the optic nerve<ref name="Article6"/>.
@@ Line 72: / Line 72: @@
 <applet load='3cap' size='300' color='black' frame='true' align='right' caption='Structure of Opsin†. The generated structure is from Chain A.'/>
 ===Topology Overview===
-The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref name="ArticleOpsin2">PMID:18563085</ref>. Also, in constrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref name="ArticleOpsin2"/>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref name="ArticleOpsin2"/>.
+The overall dimeric structure of opsin is similar to rhodopsin, with seven transmembrane helices linked by three extracellular loops and three cytoplasmic loops and a cytoplasmic Helix 8. The small differences between the topology of the two proteins include a short helical turn in the cytoplasmic loop 1 in opsin, 1.5-2.5 helical turns longer in Helix 5 for opsin in comparison to rhodopsin, and a large outward tilt of Helix 6 of opsin<ref name="ArticleOpsin2">PMID:18563085</ref>. Also, in contrast to rhodopsin, opsin has two openings of the retinal-binding pocket; one of the openings is between Helix 1 and Helix 7, and the other opening is between the extracellular ends of Helix 5 and 6. This opening is formed by the residues <scene name='Sandbox_173/Opsin_retinal_opening/1'>Isoleucine 205 and Phenylalanine 208 in Helix 5, and by the residues Phenylalanine 273 and Phenylalanine 276 in Helix 6</scene><ref name="ArticleOpsin2"/>. The two openings suggest different sites of retinal entrance and exit in retinal channeling<ref name="ArticleOpsin2"/>.
 ===Activity===