David L. Hagen
Member
Member # 323
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posted 28. February 2004 16:24
Note enabling and protection of protein folding by specialized components and processes, not a global thermodynamic minimum.
"Folding, Receptors, and Centrosomes: Structure and Function at the Molecular and Cellular Levels
David A. Agard, Ph.D. Investigator,
University of California, San Francisco
Summary: David Agard's research focuses on discovering the structural basis for biological function at the molecular and cellular levels.
The Function and Evolution of Kinetic Stability: A Study of a-Lytic Protease Folding
The central dogma in protein folding is that the native state of a protein is at the global free-energy minimum. This allows spontaneous folding to the active conformation. The extracellular bacterial protease, a-lytic protease (aLP), provides a striking counterexample in which the native state is substantially less stable than the fully unfolded molecule. Instead of being thermodynamically stabilized, aLP is trapped in its active conformation by a large energy barrier that blocks unfolding (t1/2 = 1.2 years). A further consequence is that the barrier to folding is even larger (t1/2 = 1,800 years). aLP is synthesized with a 166-residue amino-terminal pro region that solves the folding problem by both accelerating folding by nearly 10^10 and by binding tightly to the native state to shift the thermodynamic equilibrium in favor of the active enzyme. Once the protease is folded, the pro region is destroyed by proteolysis. Recent studies suggest that this unusual folding mechanism provides an optimal solution to making proteins that are themselves resistant to proteolysis. Decreasing proteolysis requires that both the barrier height and the cooperativity be increased. Thus, a protein's folding pathway can have a profound impact on the properties of the native state and not just dictate how that state is reached.
By examining other family members, we have found that the energetic cost of evolving a large unfolding barrier is high. Each factor of 30–50 improvement in unfolding rate costs a factor of 104 in foldability. Our current research focuses on uncovering the structural basis of kinetic stability. Ultrahigh-resolution x-ray crystallography (0.83 Å) indicates that a Phe in the aLP carboxyl-terminal domain is substantially bent, suggesting that strain may be a major factor in defining the barriers."
http://www.hhmi.org/research/investigators/agard.html
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