Sandbox 173: Difference between revisions

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

Andrea Gorrell, Cinting Lim

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 <applet load='1u19' size='300' color='black' frame='true' align='right' caption='11-cis Retinylidene Chromophore. The generated structures are from Chain A.'/>
-===Retinal Chromophore of Rhodospin===
+===Retinal Chromophore of Rhodopsin===
 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 name="Article19">PMID:16051215</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 name="Article20"/>.
 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 name="ReferenceArticle"/>.
-Somewhat enclosing this chromophore is a retinal binding pocket partially formed by the N-terminal domain overlaying the extracellular turns including Extracellular Helix 2, which folds into the molecular center<ref name="Article6">PMID:18692154</ref>.
+Somewhat enclosing this chromophore is a retinal binding pocket partially formed by the N-terminal domain overlaying the extracellular turns including the second extracellular loop, which folds into the molecular center<ref name="Article6">PMID:18692154</ref>.
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 ===Visual Signal Transduction===
 <applet load='1u19' size='300' color='black' frame='true' align='right' caption='Residues Involved in Activation of Rhodopsin. The generated structure is from Chain A.'/>
-====Photoisomeration of 11-''cis'' Retinal====
+====Photoisomerization of 11-''cis'' Retinal====
-The 11-''cis'' retinal (retinylidene) Schiff base functions as an [http://en.wikipedia.org/wiki/Inverse_agonist inverse agonist] and is prominently involved in the activation of rhodopsin. The primary step in rhodopsin photoactivation occurs in the photoisomeration of rhodopsin, as light energy absorbed from a photon is converted into chemical energy, As a photon is absorbed by the retina, the 11-''cis'' retinylidene ligand is switched into an all-''trans'' retinal configuration<ref name="Article2"/>. In this extremely efficient <200 fs process, the protein-binding pocket, initially fitted to accommodate the 11-''cis'' conformation of the chromophore, is preserved, which restrains the relaxation of the chromophore. The strained relaxation of conformational energy changes the protein state into the active form<ref name="Article2"/>.
+The 11-''cis'' retinal (retinylidene) Schiff base functions as an [http://en.wikipedia.org/wiki/Inverse_agonist inverse agonist] and is prominently involved in the activation of rhodopsin. The primary step in rhodopsin photoactivation occurs in the photoisomerization of rhodopsin, as light energy absorbed from a photon is converted into chemical energy. As a photon is absorbed by the retina, the 11-''cis'' retinylidene ligand is switched into an all-''trans'' retinal configuration<ref name="Article2"/>. In this extremely efficient <200 fs process, the protein-binding pocket, initially fitted to accommodate the 11-''cis'' conformation of the chromophore, is preserved, which restrains the relaxation of the chromophore. The strained relaxation of conformational energy changes the protein state into the active form<ref name="Article2"/>.
 ====Adjustment and Thermal Relaxation of the Protein====
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 ====Formation of the Metarhodopsin II State====
-Rhodopsin forms to Metarhodopsin II, the intermediate signaling state where interaction occurs with the G protein. This millisecond process is accompanied by movement in the helices, uptake of protons in the cytoplasm, and the breakage of the salt bridge between Glutamine 113 and the protonated Schiff base. The Schiff base dhttp://www.proteopedia.org/wiki/index.php?title=Sandbox_173&action=editeprotonates and the proton is transferred to the Glutamine 113 counterion, destabilizing the ground state <ref name="Article9"/>. As well, this Metarhodopsin II formation may be dependent on the protonation too of the conserved <scene name='Sandbox_173/Glu134_and_arg135/1'>Glutamine 134 that forms a salt bridge with Arginine 135</scene>, thus destabilizing the constraint on Arginine 135<ref name="Article9"/>.
+Rhodopsin forms to Metarhodopsin II, the intermediate signaling state where interaction occurs with the G protein. This millisecond process is accompanied by movement in the helices, uptake of protons in the cytoplasm, and the breakage of the salt bridge between Glutamine 113 and the protonated Schiff base. The Schiff base deprotonates and the proton is transferred to the Glutamine 113 counterion, destabilizing the ground state <ref name="Article9"/>. As well, this Metarhodopsin II formation may be dependent on the protonation too of the conserved <scene name='Sandbox_173/Glu134_and_arg135/1'>Glutamine 134 that forms a salt bridge with Arginine 135</scene>, thus destabilizing the constraint on Arginine 135<ref name="Article9"/>.
 There is positive enthalpy associated with the formation of Metarhodopsin II. This formation of the active state, also linked with the increase in entropy, is suggested to release the constraints in the helices and expose the cytoplasmic binding sites<ref name="Article9"/>. An important part of this process includes the 9-methyl group of retinal, which is suggested to provide a scaffold for proton transfers essential for the formation of the active state<ref name="Article9"/>.
-====Signalling Cascade and Polarization of the Cell Membrane====
+====Signaling Cascade and Polarization of the Cell Membrane====
 [[image:RhodopsinTransducinComplex.jpg|thumb|left|Rhodopsin interaction with transducin.]]
 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>.