FKBP Family Proteins: Immunophilins with Versatile Biological Functions
FKBP Family Proteins: Immunophilins with Versatile Biological Functions
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DOI：
10.1159/000123041
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Yoon, Ho Sup
中科院分区：
文献类型：
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作者：
Kang, Cong Bao;Ye, Hong;Yoon, Ho Sup
FK506结合蛋白（FK506 binding protein， FKBP）是一类与免疫抑制药物如FK506、雷帕霉素和环孢素a结合的高度保守蛋白家族，FK506是两种主要的免疫亲和蛋白之一，FKBP家族的大多数成员与FK506结合并表现出肽基脯氨酸顺式/反式异构酶（PPIase）活性。小分子量的FKBP家族成员只包含fk506结合域，而大分子量的FKBP家族成员拥有额外的结构域，如四肽重复结构域、钙调蛋白结合结构域和跨膜结构基。FKBPs参与多种生化过程，包括蛋白质折叠、受体信号传导、蛋白质转运和转录。当FKBP家族蛋白与其配体配合时，在t细胞活化中发挥重要的功能作用。近年来，亲免疫蛋白通过与受体或蛋白的分子相互作用在蛋白质运输和细胞凋亡中的作用逐渐被发现。此外，亲免疫蛋白配体在治疗神经退行性疾病中的治疗意义已经积累起来。无免疫抑制活性的FK506及其衍生物与典型FKBP成员（如FKBP12）的保守活性位点结合，显示PPIase活性。这些亲免疫蛋白配体在帕金森病、痴呆和脊髓损伤的动物模型中显示出不同的疗效，其中典型的亲免疫蛋白作为伴侣起作用，与蛋白质折叠和氧化应激调节有关。另一方面，在非典型FKBP成员如FKBP38中，FK506结合位点不保守，既没有PPIase活性，也没有对FK506的亲和力。有趣的是，在大鼠局灶性脑缺血模型中，FKBP家族非规范成员的小分子介导抑制似乎引起神经元保护并诱导神经元干细胞增殖。目前，其作用机制尚不清楚。本文综述了典型和非典型FKBP家族成员的分子特征及其配体在神经保护和神经营养活性中的生物学功能。版权所有2008 S. Karger AG，巴塞尔
Immunophilins consist of a family of highly conserved proteins binding with immunosuppressive drugs such as FK506, rapamycin and cyclosporin A. FK506-binding protein (FKBP) is one of two major immunophilins and most of FKBP family members bind FK506 and show peptidylprolyl cis/trans isomerase (PPIase) activity. Small size FKBP family members contain only FK506-binding domain, while FKBPs with large molecular weights possess extra domains such as tetratricopeptide repeat domains, calmodulin binding and transmembrane motifs. FKBPs are involved in several biochemical processes including protein folding, receptor signaling, protein trafficking and transcription. FKBP family proteins play important functional roles in the T-cell activation, when complexed with their ligands. The roles of immunophilins in protein transportation and apoptosis through their molecular interactions with receptors or proteins have emerged recently. Moreover, therapeutic implications of immunophilin ligands in treating neurodegenerative disorders have been accumulating. FK506 and its derivatives with no immunosuppressive activities bind to the conserved active sites of the canonical FKBP members such as FKBP12, which shows PPIase activity. These immunophilin ligands show variable efficacy in animal models for Parkinson's disease, dementia, and spinal cord injury, where the canonical immunophilins function as chaperones and are associate with the protein folding and modulation of oxidative stress. On the other hand, in the noncanonical FKBP members such as FKBP38, FK506-binding site is not conserved and shows neither PPIase activity nor affinity to FK506. Interestingly, the small molecule-mediated inhibition of the noncanonical member of FKBP family appears to cause neuronal protection and induce proliferation of neuronal stem cells in a rat focal cerebral ischemia model. Currently, the mechanisms of actions remain unclear. This review focuses on molecular characteristics of the canonical and noncanonical FKBP family members and the biological functions of their ligands in performing neuroprotective and neurotrophic activities. Copyright (C) 2008 S. Karger AG, Basel