Sandbox 16: Difference between revisions
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== Folding == | == Folding == | ||
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 Pro region overcomes the barrier to folding by providing a catalyzed pathway in which the transition state 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<sub>1/2</sub>~1.2 years). Below shows the free energy diagrams summarizing the difference between the folding landscape of a typical thermodynamically stable protein (left) and that of the kinetically stable αLP (right). The free-energy diagram of αLP folding is shown with (dotted blue line) and without (solid black line) its Pro region (P). In the absence of its Pro region, unfolded αLP (U) spontaneously folds to a partially folded intermediate (I), which progresses at a very slow rate (t<sub>1/2</sub></p>~1800 years) to N through a very high transition state (TS). | 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 Pro region overcomes the barrier to folding by providing a catalyzed pathway in which the transition state 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<sub>1/2</sub>~1.2 years). Below shows the free energy diagrams summarizing the difference between the folding landscape of a typical thermodynamically stable protein (left) and that of the kinetically stable αLP (right). The free-energy diagram of αLP folding is shown with (dotted blue line) and without (solid black line) its Pro region (P). In the absence of its Pro region, unfolded αLP (U) spontaneously folds to a partially folded intermediate (I), which progresses at a very slow rate (t<sub>1/2</sub></p>~1800 years) to N through a very high transition state (TS). | ||
Rainbow ALp <scene name='Sandbox_16/Thesis_pic/1'>TextToBeDisplayed</scene> | |||
[[Image:therm vs kinetic.jpg]] | [[Image:therm vs kinetic.jpg]] | ||
