Sandbox Reserved 489: Difference between revisions

The precursor of renin is a 406 amino acid residue protein.  <scene name='Sandbox_Reserved_489/Signal_domain/1'>Residues 1-23</scene> are a signal peptide sequence and residues 24-66 are cleaved to produce the mature 340 amino acid residue <scene name='Sandbox_Reserved_489/Mature_renin/1'>mature renin</scene>.  The secondary structural elements of renin include 29 <scene name='Sandbox_Reserved_489/Betasheetscolors/1'> antiparallel β sheets</scene>, 3 <scene name='Sandbox_Reserved_489/Betabridges/1'> β bridges</scene>, 4 <scene name='Sandbox_Reserved_489/Alphahelixes/1'> α helices</scene>, <scene name='Sandbox_Reserved_489/310heleices/1'> 2 </scene>3₁₀<scene name='Sandbox_Reserved_489/310heleices/1'> helices</scene>, and <scene name='Sandbox_Reserved_489/Turns/1'>18 turns</scene>.  The most impressive structural feature of renin is the antiparallel<scene name='Sandbox_Reserved_489/Betasheetspiral/1'> β sheet</scene> that forms the two similar lobes of renin.  <scene name='Sandbox_Reserved_489/Hydrophobichydrophillic/1'>Hydrophilic (blue) and hydrophobic (red) residues</scene> are located primarily on the outside and inside portions of renin respectively.  The most important structure is the <scene name='Sandbox_Reserved_489/Hydrophobicactivesite/1'>hydrophobic pocket</scene> located in the active site that allows substrate binding. The active site of renin contains two essential <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>aspartate residues</scene>.  Renin has <scene name='Sandbox_Reserved_489/Catalyticmotifs/1'>two catalytic motifs</scene> after each of the two aspartate residues.  Renin also uses a <scene name='Sandbox_Reserved_489/Activesiteflap/1'>active site flap</scene>, a β hairpin structure, that open and closes to uncover or cover the active site.

The substrate of renin, angiotensinogen, is a 452 amino acid residue in humans.  Renin utilizes two aspartate residues in the <scene name='Sandbox_Reserved_489/Activesiteasps2/2'>active site</scene> to cleave the peptide bond between leucine and valine residues on angiotensinogen.  Angiotensin I is an inactive short peptide of 10 amino acids that is produced by the renin cleavage reaction.  The close proximity of the two aspartate allows the acid-base hydrolysis mechanism to cleave the peptide bond.  Because the aspartate residues are close together one residue has a higher pKa and the other residue has a lower pKa.  The mechanism of the catalysis is an acid-base transfer of water between the two aspartate residues.  There is a water molecule associated with the two aspartate residues in the active site and also a water associated with the peptide bond that is cleaved.  Initially one aspartate residue carbonyl is deprotonated and the other is protonated.  The deprotonated aspartate removes a proton from water allowing the water to attack the carbonyl of the peptide bond in the substrate forming a tetrahedral oxyanion intermediate on the substrate.  Rearrangement of the intermediate causes protonation of the amide on the substrate completing the cleavage reaction.  A concerted mechanism of action has also been proposed that states the active site aspartate and water attack the scissle peptide bond in a single step with no covalent tetrahedral intermediate, while still forming the tetrahedral transition state.