Dr. Caffrey et al., A method to predict residues conferring functional differences between related proteins: Application to MAP kinase pathways, PROTEIN SCI, 9(4), 2000, pp. 655-670
Physicochemical properties are potentially useful in predicting functional
differences between aligned protein subfamilies. We present a method that c
onsiders physicochemical properties from ancestral sequences predicted to h
ave given rise to the subfamilies of interest by gene duplication. Comparis
on between two map kinases subfamilies, p38 and ERK, revealed a region that
had an excess of change in properties after gene duplication followed by c
onservation within the two subfamilies. This region corresponded to that ex
perimentally defined as important for substrate and pathway specificity. Th
e derived scores for the region of interest were found to differ significan
tly in their distribution compared to the rest of the protein when the Kolm
ogorov-Smirnov test was applied (p = 0.005). Thus, the incorporation of anc
estral physicochemical properties is useful in predicting functional differ
ences between protein subfamilies. In addition, the method was applied to t
he MKK and MAPK components of the p38 and JNK pathways. These proteins show
ed a similar pattern in their evolution and regions predicted to confer fun
ctional differences are discussed.