Sandbox 16: Difference between revisions

<p>The <scene name='Sandbox_16/Alp-1/2'>secondary structure</scene> contains the double β-barrel motif (colored yellow) that is characteristic of the chymotrypsin family as well as an active site containing the <scene name='Sandbox_16/Alp-1/6'>"catalytic triad"</scene> -  His 57, Asp 102, and Ser 195 - that is responsible for proteolysis. The preference for αLP to cleave substrates on the C-terminal side of small hydrophobic residues, such as Alanine and Valine is mostly due to <scene name='Sandbox_16/Alp-1/3'>three residues in  the S1 pocket</scene> consisting of Met 190, Met 213, and Val 218<ref>PMID:9232638</ref>. In contrast to its mammalian homologs like trypsin and chymotrypsin, αLP is synthesized with a 166 residue N-terminal Pro region that plays an obligatory role in the proper folding of its 198 residue protease domain<ref>PMID:2646278</ref>. The barrier to folding is overcome by a pro region, which provides a catalyzed pathway in which the barrier to folding is lowered by 18.2 kcal/mol<ref>PMID:9796818</ref>. The product of this folding is not active αLP but an inhibitory complex, N*P. The release of active αLP requires the removal of the Pro region via proteolysis, which occurs naturally. This leaves the native αLP, a metastable state with a large barrier to unfolding (t_1/2~1.2 years). Below shows the free energy diagram summarizing the difference between the folding landscape of a typical thermodynamically stable protein (left) and that of αLP (right). The dotted blue line indicates the folding landscape in the presence of the Pro region.