Assessment of conformational parameters as predictors of limited proteolytic sites in native protein structures.
Despite the importance of limited proteolysis in biological systems it is often difficult to rationalize why a proteinase hydrolyses a particular bond, given a simple sequence specificity alone. Understanding of the structural properties limiting the proteolysis represents a first step on the pathway to control and manipulation of this phenomena. An expanded set of nick-sites in proteins of known tertiary structure, cut by both narrow and broad specificity proteinases, has been generated yielding a robust data set of strictly limited sites. A critical evaluation of an expanded set of conformational parameters revealed a strong correlation with limited proteolytic sites, although they are only modest predictors in isolation. The overall predictive power is significantly improved when the conformational parameters are combined in a weighted predictive scheme that permits their relative importance to be compared via a Metropolis search protocol. A subset of the parameters performs equally well demonstrating the key determinants of susceptibility. The derived predictive algorithm has been made available via the internet. Its utility for predicting other surface-correlated features is also discussed.
Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, UK.
S J
SJ
Hubbard
R J
RJ
Beynon
J M
JM
Thornton
D000465:Algorithms; D000595:Amino Acid Sequence; D003195:Computer Communication Networks; D006860:Hydrogen Bonding; D010447:Peptide Hydrolases / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D012984:Software; D013696:Temperature
D011506:Proteins; D010447:Peptide Hydrolases