Sandbox 173: Difference between revisions
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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.'/> | <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 | ===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"/>. | 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"/>. | ||
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===Visual Signal Transduction=== | ===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.'/> | <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.'/> | ||
==== | ====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 | 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==== | ====Adjustment and Thermal Relaxation of the Protein==== | ||
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====Formation of the Metarhodopsin II State==== | ====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 | 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"/>. | 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"/>. | ||
==== | ====Signaling Cascade and Polarization of the Cell Membrane==== | ||
[[image:RhodopsinTransducinComplex.jpg|thumb|left|Rhodopsin interaction with transducin.]] | [[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>. | 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>. | ||