Sewell T J, Lam E, Martin M M, Leszyk J, Weidner J, Calaycay J, Griffin P, Williams H, Hung S, Cryan J
Department of Immunology Research, Merck Research Laboratories, Rahway, New Jersey 07065.
J Biol Chem. 1994 Aug 19;269(33):21094-102.
FK-506, a potent immunosuppressive drug, acts during the commitment phase of T-lymphocyte activation to block a subset of calcium-associated events necessary for transcription of certain early lymphokine genes. The drug binds to an abundant, cytosolic 11.8-kDa protein termed the FK-506-binding protein (FKBP12). The FKBP12.FK-506 complex inhibits calcineurin, a calcium-dependent phosphatase that is a component of the signal transduction pathway leading to early lymphokine gene transcription. FKBP12 is one member of a growing gene family. Prior to this report, all other FKBP family members had been irrelevant to the mechanism of action of FK-506 because no other FKBP.FK-506 complexes were able to bind and inhibit calcineurin. Here, we report the purification and characterization of a novel FK-506-binding protein, FKBP12.6. Having 85% amino acid sequence identity to FKBP12, FKBP12.6 is, among the FKBPs, most closely related to FKBP12. When complexed with FK-506, FKBP12.6 binds to and inhibits calcineurin, making it only the second FKBP discovered thus far to do so. The ability to inhibit calcineurin establishes the potential relevance of FKBP12.6 to the immunosuppressive or toxic side effects of FK-506.
FK-506是一种强效免疫抑制药物，在T淋巴细胞激活的起始阶段发挥作用，阻断某些早期淋巴因子基因转录所需的一部分与钙相关的事件。该药物与一种丰富的、胞质中的11.8 kDa蛋白结合，这种蛋白被称为FK-506结合蛋白（FKBP12）。FKBP12.FK-506复合物抑制钙调神经磷酸酶，这是一种钙依赖性磷酸酶，是导致早期淋巴因子基因转录的信号转导途径的一个组成部分。FKBP12是一个不断扩大的基因家族的成员之一。在本报告之前，所有其他FKBP家族成员与FK-506的作用机制均无关，因为没有其他FKBP.FK-506复合物能够结合并抑制钙调神经磷酸酶。在此，我们报告了一种新型FK-506结合蛋白FKBP12.6的纯化和特性。FKBP12.6与FKBP12有85%的氨基酸序列同一性，在FKBP中，它与FKBP12的关系最为密切。当与FK-506复合时，FKBP12.6能结合并抑制钙调神经磷酸酶，这使其成为迄今为止发现的第二种具有这种能力的FKBP。抑制钙调神经磷酸酶的能力确立了FKBP12.6与FK-506的免疫抑制或毒性副作用之间的潜在关联。
