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Abstract：
The Hsp90 chaperone promotes folding and activation of hundreds of client proteins in the cell through an ATP-dependent conformational cycle guided by distinct cochaperone regulators. The FKBP51 immunophilin binds Hsp90 with its tetratricopeptide repeat (TPR) domain and catalyzes peptidyl-prolyl isomerase (PPIase) activity during folding of kinases, nuclear receptors, and tau. Here we determined the cryoelectron microscopy (cryo-EM) structure of the human Hsp90:FKBP51:p23 complex to 3.3 Å, which, together with mutagenesis and crosslinking analyses, reveals the basis for cochaperone binding to Hsp90 during client maturation. A helix extension in the TPR functions as a key recognition element, interacting across the Hsp90 C-terminal dimer interface presented in the closed, ATP conformation. The PPIase domain is positioned along the middle domain, adjacent to Hsp90 client binding sites, whereas a single p23 makes stabilizing interactions with the N-terminal dimer. With this architecture, FKBP51 is positioned to act on specific client residues presented during Hsp90-catalyzed remodeling.
摘要：
Hsp90伴侣通过由不同的伴侣调节因子引导的ATP依赖性构象循环促进细胞中数百种客户蛋白的折叠和激活。FKBP51免疫亲素结合Hsp90及其四三肽重复序列（TPR）结构域，并在激酶折叠过程中催化肽基脯氨酸异构酶（PPIase）活性，核受体,还有tau.在这里，我们确定了人类Hsp90：FKBP51：p23复合物的低温电子显微镜（cryo-EM）结构为3.3，which,连同诱变和交联分析，揭示了在客户成熟过程中伴侣与Hsp90结合的基础。TPR中的螺旋延伸作为关键识别元件，在封闭的Hsp90C端二聚体界面上相互作用，ATP构象。PPIase结构域位于中间结构域,与Hsp90客户端结合位点相邻，而单个p23与N端二聚体产生稳定的相互作用。有了这个架构，FKBP51被定位为作用于在Hsp90催化的重塑期间呈现的特定客户残基。
