Proximity effects on the protein domain level: engineering prolyl isomerases through combinatorial biochemistry.

Peptidyl isomerases (PPIs) catalyze the backbone trans to cis interconversion of AA–Pro (AA: amino acid residue that precedes Pro) bonds. This reaction is particularly important for folding proteins since only proper cis-Pro configuration at certain (rather rare) key positions allows for attaining the native and thus functional three-dimensional structure. While some PPIs, such as FKBP12, recognize and catalyze isomerization of short peptides without participating in protein folding, many PPIs are composed of a prolyl isomerase domain that is responsible for the chemistry of the isomerization process and an additional domain that recognizes and transiently binds unfolded or partially folded polypeptide chains. A prime example of this architecture is the trigger factor, which is associated with the ribosome via an additional small attachment site and awaits newly synthesized polypeptide chains to assist in proline isomerization if needed [1,2]. Other PPIs that are also composed of a catalytic site and additional chaperone domain are many proteins from the FKBP family (FKBP12 is rather an exception here) or SurA, SlyD, and parvulins among others [3].