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Publication Abstract from PubMed

Ultrahigh-resolution (< 1.0 A) structures have revealed unprecedented and unexpected details of molecular geometry, such as the deformation of aromatic rings from planarity. However, the functional utility of such energetically costly strain is unknown. The 0.83 A structure of alpha-lytic protease (alphaLP) indicated that residues surrounding a conserved Phe side-chain dictate a rotamer which results in a approximately 6 degrees distortion along the side-chain, estimated to cost 4 kcal/mol. By contrast, in the closely related protease Streptomyces griseus Protease B (SGPB), the equivalent Phe adopts a different rotamer and is undistorted. Here, we report that the alphaLP Phe side-chain distortion is both functional and conserved in proteases with large pro regions. Sequence analysis of the alphaLP serine protease family reveals a bifurcation separating those sequences expected to induce distortion and those that would not, which correlates with the extent of kinetic stability. Structural and folding kinetics analyses of family members suggest that distortion of this side-chain plays a role in increasing kinetic stability within the alphaLP family members that use a large Pro region. Additionally, structural and kinetic folding studies of mutants demonstrate that strain alters the folding free energy landscape by destabilizing the transition state (TS) relative to the native state (N). Although side-chain distortion comes at a cost of foldability, it suppresses the rate of unfolding, thereby enhancing kinetic stability and increasing protein longevity under harsh extracellular conditions. This ability of a structural distortion to enhance function is unlikely to be unique to alphaLP family members and may be relevant in other proteins exhibiting side-chain distortions.

Functional modulation of a protein folding landscape via side-chain distortion.,Kelch BA, Salimi NL, Agard DA Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9414-9. Epub 2012 May 25. PMID:22635267^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.