PEST SEQUENCES IN PROTEINS INVOLVED IN CYCLIC-NUCLEOTIDE SIGNALING PATHWAYS

There is growing evidence that PEST sequences act as proteolytic recog nition signals within polypeptides. PEST sequences are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and can be iden tifed by the PEST-FIND program. Both the catalytic and regulatory subu nits of the cAMP-dependent protein kinase have been shown to have cond itional PEST sequences which are exposed upon cAMP binding to the enzy me. cAMP binding leads to rapid dissociation of C- and R-subunits, and both subunits have increased sensitivity to proteolysis. It is not kn own whether other proteins that participate in the cyclic nucleotide s ignalling pathway have PEST regions in thier amino acid sequences. The refore, we have screened amino acid sequences of proteins that are dir ectly involved in cyclic nucleotide cascade, including cGMP-dependent protein kinases, anchoring proteins for cAMP-dependent protein kinase, cyclic nucleotide-gated ion channels, and cyclic nucleotide phosphodi esterases, for PEST sequences using the PEST-FIND program. Many PEST s equences with high scores have been identified in these proteins. The occurence of the PEST sequences is very high in proteins involved in c yclic nucleotide signalling pathways (similar to 80%). This value is m uch higher than the percentage (10%) of PEST sequences that can be fou nd in the primary structures of the proteins listed in the data bank. This frequent occurence of PEST sequences in proteins involved in cycl ic nucleotide action and metabolism suggests an important role of prot eolysis of these key proteins of signal transduction.