Sandbox 173: Difference between revisions
Cinting Lim (talk | contribs) No edit summary |
Cinting Lim (talk | contribs) No edit summary |
||
| Line 2: | Line 2: | ||
==Introduction== | ==Introduction== | ||
===Rhodopsin=== | ===Rhodopsin=== | ||
Rhodopsin, a homodimeric protein, is a highly characterized [http://en.wikipedia.org/wiki/G_protein-coupled_receptor G protein-coupled receptor] found in membranous disks of the outer segments of rod and cone cells, though rhodopsin is more concentrated in rod cells which are sensitive to light but cannot discriminate colors. Rhodopsin is part of the superfamily of G protein-coupled receptors that mediate responses to visual, olfactory, hormonal, and neurotransmitter signals among others<ref name="Article1">PMID:20004206</ref>. Rhodopsin is involved in visual signal transduction and the visual system in classic G protein-coupled receptor mechanisms<ref> | Rhodopsin, a homodimeric protein, is a highly characterized [http://en.wikipedia.org/wiki/G_protein-coupled_receptor G protein-coupled receptor] found in membranous disks of the outer segments of rod and cone cells, though rhodopsin is more concentrated in rod cells which are sensitive to light but cannot discriminate colors. Rhodopsin is part of the superfamily of G protein-coupled receptors that mediate responses to visual, olfactory, hormonal, and neurotransmitter signals among others<ref name="Article1">PMID:20004206</ref>. Rhodopsin is involved in visual signal transduction and the visual system in classic G protein-coupled receptor mechanisms<ref name="Article12">PMID:11891118</ref>. | ||
===G Protein-Coupled Receptors=== | ===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>Article 20</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 | 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>Article 20</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>Article 20</ref>. 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>Article 20</ref>. | ||
| Line 11: | Line 11: | ||
<applet load='1u19' size='300' color='black' frame='true' align='right' caption='Structure of Rhodopsin. The generated structures are from Chain A.'/> | <applet load='1u19' size='300' color='black' frame='true' align='right' caption='Structure of Rhodopsin. The generated structures are from Chain A.'/> | ||
===Rhodopsin Architecture=== | ===Rhodopsin Architecture=== | ||
Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail<ref | Rhodopsin consists of seven mostly α-helical transmembrane domains (H1-H7) linked sequentially by extracellular and cytoplasmic loops (E1-E3 and C1-C3 respectively), with the extracellular amino-terminal tail and the cytoplasmic carboxyl-terminal tail<ref name="Article12"/>. Four of the helices are tilted and three of the helices are approximately perpendicular to the membrane plane<ref name="Article4">PMID:9199406</ref>. There is notable interaction between the four extracellular domains, but only a few associations are observed with the cytoplasmic domains<ref name="Article9">PMID:11343925</ref>. Helix 7 is close to being elongated around the Lysine 296 retinal attachment site, and also contains the residues Proline 291 and Proline 303, with Proline 303 being part of a conserved motif<ref name="Article9"/>. Near the retinal region, there is a <scene name='Sandbox_173/Beta_4_strand_and_retinal/2'>β4 strand (Serine 186-Cysteine 187-Glycine 188-Isoleucine 189)</scene> within the Extracellular Helix 2 that runs almost parallel to the chromophore held in place and is stabilized by the essential conserved | ||
<scene name='Sandbox_173/Disulfide_bond/4'>disulfide bond between Cysteine 110 and Cysteine 187</scene>. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191<ref | <scene name='Sandbox_173/Disulfide_bond/4'>disulfide bond between Cysteine 110 and Cysteine 187</scene>. This loop also potentially contacts the chromophore through Glutamine 181 and Tyrosine 191<ref name="Article12"/>. | ||
<scene name='Sandbox_173/Water_molecules/1'>Water molecules</scene> are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility should rearrangement occur<ref>Original article</ref>. | <scene name='Sandbox_173/Water_molecules/1'>Water molecules</scene> are observed to be located in the extracellular domains of rhodopsin; specifically, the water molecules around the second extracellular loop between Helix 4 and 5 solvate the loop when the loop interacts with the retinal chromophore and possibly contribute to its flexibility should rearrangement occur<ref>Original article</ref>. | ||
There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from <scene name='Sandbox_173/Helix_8/1'>Asparagine 310 to Cysteine 323</scene> and is formed from the C-terminal tail anchoring to the membrane by | There is the presence of a cationic amphipathic Helix 8, known as the fourth cytoplasmic loop, that spans from <scene name='Sandbox_173/Helix_8/1'>Asparagine 310 to Cysteine 323</scene> and is formed from the C-terminal tail anchoring to the membrane by | ||
<scene name='Sandbox_173/Cys322_and_cys323/1'>Cysteine 322 and Cysteine 323</scene>, which are <scene name='Sandbox_173/Palmitates/3'>palmitoylated</scene>. This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding<ref name="Article9"/>, as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions<ref | <scene name='Sandbox_173/Cys322_and_cys323/1'>Cysteine 322 and Cysteine 323</scene>, which are <scene name='Sandbox_173/Palmitates/3'>palmitoylated</scene>. This helix runs approximately parallel to the cytoplasmic surface and is involved in Gtγ binding<ref name="Article9"/>, as well as the modulation of rhodopsin-transducin interactions and rhodopsin-phospholipid interactions<ref name="Article12"/>. | ||
A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation<ref name="Article10"/>. | A metal zinc ion bridge chelated by histidine side-chains and connected to the cytoplasmic ends of Helix 3 and 6 is observed to prevent receptor activation. This perhaps indicates that separation of these cytoplasmic ends would contribute to rhodopsin activation<ref name="Article10"/>. | ||
| Line 26: | Line 26: | ||
===Retinal Chromophore of Rhodospin=== | ===Retinal Chromophore of Rhodospin=== | ||
Rhodopsin consists of an opsin [http://en.wikipedia.org/wiki/Apoprotein apoprotein] and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in <font color='#FFFF00'>yellow</font>) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref | Rhodopsin consists of an opsin [http://en.wikipedia.org/wiki/Apoprotein apoprotein] and a <scene name='Sandbox_173/11-cis_retinylidene_structure/1'>11-cis retinylidene chromophore</scene> in its active site. Rhodopsin is bound covalently to the 11-''cis'' retinal, the chromophore or "ligand," (shown in <font color='#FFFF00'>yellow</font>) and this retinal is found in deeply in the core of the helices, in a hydrophobic site, parallel to the lipid bilayer<ref>Article 19</ref>. Comparatively, it is situated more towards the extracellular planes of the membrane bilayer <ref name="Article12"/>. The retinal is attached in the active site of rhodopsin through a protonated Schiff base (an N-substituted imine) bond to the ε-amino group of Lysine 296 residue (shown in <font color='#00FF00'>green</font>) on the C-terminal Helix 7, with this linkage creating a positive charge on the chromophore <ref name="Article4"/>. The protonated Schiff base of rhodopsin is stabilized through <scene name='Sandbox_173/Glu113/1'>Glutamine 113</scene> residue electrostatic interaction with the counterion, holding the inactive rhodopsin in its state<ref>Article 20</ref>. | ||
As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref name="Article2">PMID:16962138</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation <ref>Original article</ref>. | As this ligand is bound in the 12-s-''trans'' conformation, there arises the non-bonding interactions between the C-13 methyl group and C-10 hydrogen that contribute to non-planarity. This leads to the ability of the chromophore polyene tail to undergo fast photoisomerization around the C-11=C-12 double bond during light-induced activation<ref name="Article2">PMID:16962138</ref>. Also, it is found that the C-11=C-12 double bond is pre-twisted in the ground state of rhodopsin, which is partly attributed to the C20 methyl group attached to C13 through interaction with Tryptophan 265. This pre-twist may give insight on the features of isomerization about this bond upon light activation <ref>Original article</ref>. | ||