Book of Abstracts: Albany 2003
June 17-21 2003
Enzymes are Ordered and Signaling Proteins are Intrinsically Disordered
Anecdotal observations suggest that cell-signaling proteins are rich in intrinsically unfolded or disordered protein. Additionally, application of predictors of intrinsic disorder to various genomes spanning the 3 kingdoms of life indicate a large jump in intrinsic disorder for the eukaryotes, perhaps reflecting a greater use of disordered proteins for signaling and regulation in organisms with nucleated cells. To further test for an association between signaling and disorder, four protein databases were analyzed. The results indicated substantially more intrinsic disorder in cancer-associated and signaling proteins as compared to two control sets, thus reinforcing the importance of intrinsic disorder in signal transduction. The disorder analysis was extended to 11 functionally diverse categories of proteins from Swiss-Prot. Proteins involved in metabolism, biosynthesis and degradation are predicted to have at least two-fold less disorder than regulatory and cancer-associated proteins, and these predictions are supported by the frequency of occurrence of homologous proteins in the Protein Data Bank. On the other hand, a wide variety of evidence suggests that the active sites of enzymes have to be pre-ordered in order to bind preferentially to their cognate transition states. From these observations, we propose that ordered proteins evolved for catalysis and disordered proteins for signaling.
A. Keith Dunker
School of Molecular Biosciences