Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism

PIN1 is an essential and conserved mitotic peptidyl-prolyl isomerase (PPIase) that is distinct from members of two other families of conventional PPIases, cyclophilins and FKBPs (FK-506 binding proteins). In response to their phosphorylation during mitosis, PIN1 binds and regulates members of a highly conserved set of proteins that overlaps with antigens recognized by the mitosis-specific monoclonal antibody MPM-2. PIN1 is here shown to be a phosphorylation-dependent PPIase that specifically recognizes the phosphoserine-proline or phosphothreonine-proline bonds present in mitotic phosphoproteins. Both PIN1 and MPM-2 selected similar phosphorylated serine-proline-containing Peptides, providing the basis for the specific interaction between PIN1 and MPM-2 antigens. PIN1 preferentially isomerized proline residues preceded by phosphorylated serine or threonine with up to 1300-fold selectivity compared with unphosphorylated Peptides. PIN1 may thus regulate mitotic progression by catalyzing sequence-specific and phosphorylation-dependent proline isomerization.