Structure of the N-terminal domain of human FKBP52
Structure of the N-terminal domain of human FKBP52
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DOI：
10.1107/s0907444902017523
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发表时间：
2003-01-01
影响因子：
2.2
通讯作者：
Rao, ZH
中科院分区：
文献类型：
--
作者：
Li, PY;Ding, Y;Rao, ZH
FKBP 52是FK 506结合蛋白家族（FKBP）的成员。FKBP 52的N-末端结构域（FKBP 52-N;残基1-140）负责肽基-脯氨酰异构酶活性和FK 506的结合。这里，FKBP 52-N的晶体结构已经通过分子置换至2.4埃来确定。FKBP 52-N由六链反平行β-折叠定义，其在短α-螺旋周围具有右旋扭曲，其结构类似于FKBP 12。FKBP 52-N能够以与FKBP 12类似的方式结合FK 506。两个环区（残基70-76和108-127）的变异性是FKBP 52-N和FKBP 12之间特异性差异的主要原因。FKBP 12中对应于Gly 89的Pro 120改变限制了环（残基108-127）和FK 506之间的构象适应，并降低了FK 506亲和力，而对应于FKBP 12的Ile 90的Lys 121取代破坏了FKBP 52-N和钙调磷酸酶之间的关键相互作用。从多肽链中严格保守氨基酸的位置可以推断，FKBP的PPI酶结构域的整体构象的维持对于PPI酶活性是必需的。FKBP 52-N的N-末端区域和β-折叠形成疏水补丁，其可能负责结合靶蛋白，如动力蛋白或PAHX。
FKBP52 is a member of the FK506-binding protein family (FKBPs). The N-terminal domain of FKBP52 (FKBP52-N; residues 1-140) is responsible for peptidyl-prolyl isomerase activity and binding of FK506. Here, the crystal structure of FKBP52-N has been determined by molecular replacement to 2.4 Angstrom. FKBP52-N is defined by a six-stranded antiparallel beta-sheet wrapping with a right-handed twist around a short alpha-helix, an architecture similar to that of FKBP12. FKBP52-N is able to bind FK506 in a similar way to FKBP12. The variability in two loop regions (residues 70-76 and 108-127) is the principal reason for the specificity differences between FKBP52-N and FKBP12. The Pro120 change corresponding to Gly89 in FKBP12 limits the conformational adaptation between the loop (residues 108-127) and FK506 and decreases the FK506 affinity, while the Lys121 substitution corresponding to Ile90 of FKBP12 destroys a key interaction between FKBP52-N and calcineurin. It can be inferred from the locations of strictly conserved amino acids in the polypeptide chain that the maintenance of the overall conformation of the PPIase domains of FKBPs is essential for the PPIase activity. The N-terminal region and beta-sheets of FKBP52-N forms a hydrophobic patch which may be responsible for the binding of target proteins such as dynein or PAHX.