Ivery M T
Faculty of Pharmacy, University of Sydney, N.S.W. 2006, Australia.
Med Res Rev. 2000 Nov;20(6):452-84. doi: 10.1002/1098-1128(200011)20:6<452::aid-med2>3.0.co;2-6.
Peptidylprolyl isomerases (PPIases) are a group of cytosolic enzymes first characterized by their ability to catalyze the cis-trans isomerization of cis-peptidylprolyl bonds. Subsequently, some PPIases were also identified as the initial targets of the immunosuppressant drugs-cyclosporin A (CsA), FK506, and rapamycin-have been called immunophilins. Immunophilins have been found to be both widely distributed and abundantly expressed leading to suggestions that they may play a general role in cellular biochemistry. However, the nature of this role has been difficult to elucidate and is still controversial in vivo. A number of roles for these enzymes have been identified in vitro including the ability to catalyze the refolding of partly denatured proteins and stabilize multiprotein complexes such as Ca(2+) channels, inactive steroid receptor complexes, and receptor protein tyrosine kinases. Generally, these effects appear to depend on the ability of immunophilins to selectively bind to other proteins. This review will examine in detail experimental and structural investigations of the mechanism of PPIase activity for both FKBPs and cyclophilins and suggest a mechanism for these enzymes, which depends on their ability to recognize a specific peptide conformation rather than sequence. Examination of structures of immunophilin-protein complexes will then be used to further suggest that the ability of these enzymes to recognize specific peptide conformations is central to the formation of these complexes and may constitute a general function of immunophilin enzymes. The binding of ligand to immunophilins will also be shown to stabilize specific conformations in surface loops of these proteins that are observed to play a critical role in a number of immunophilin-protein complexes suggesting that the immunophilins may constitute a class of ligand-triggered selective protein binders.
肽脯氨酰顺反异构酶（PPIases）是一类胞质酶，最初因其催化顺式肽脯氨酰键的顺反异构化能力而被鉴定。随后，一些PPIases也被确定为免疫抑制剂环孢素A（CsA）、FK506和雷帕霉素的初始靶点，这些酶被称为亲免素。已发现亲免素广泛分布且大量表达，这表明它们可能在细胞生物化学中发挥普遍作用。然而，这种作用的本质很难阐明，在体内仍存在争议。在体外已确定这些酶的多种作用，包括催化部分变性蛋白质的重折叠以及稳定多蛋白复合物，如钙（2+）通道、无活性的类固醇受体复合物和受体蛋白酪氨酸激酶。一般来说，这些作用似乎取决于亲免素选择性结合其他蛋白质的能力。本综述将详细研究FKBPs和亲环素的PPIase活性机制的实验和结构研究，并提出这些酶的一种机制，该机制取决于它们识别特定肽构象而非序列的能力。对亲免素 - 蛋白质复合物结构的研究将进一步表明，这些酶识别特定肽构象的能力对于这些复合物的形成至关重要，可能构成亲免素酶的一项普遍功能。还将表明配体与亲免素的结合会稳定这些蛋白质表面环中的特定构象，这些构象在许多亲免素 - 蛋白质复合物中起关键作用，这表明亲免素可能构成一类配体触发的选择性蛋白质结合剂。
