Soldano Karen L, Jivan Arif, Nicchitta Christopher V, Gewirth Daniel T
Departments of Biochemistry and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
J Biol Chem. 2003 Nov 28;278(48):48330-8. doi: 10.1074/jbc.M308661200. Epub 2003 Sep 11.
GRP94, the endoplasmic reticulum (ER) paralog of the chaperone Hsp90, plays an essential role in the structural maturation or secretion of a subset of proteins destined for transport to the cell surface, such as the Toll-like receptors 2 and 4, and IgG, respectively. GRP94 differs from cytoplasmic Hsp90 by exhibiting very weak ATP binding and hydrolysis activity. GRP94 also binds selectively to a series of substituted adenosine analogs. The high resolution crystal structures at 1.75-2.1 A of the N-terminal and adjacent charged domains of GRP94 in complex with N-ethylcarboxamidoadenosine, radicicol, and 2-chlorodideoxyadenosine reveals a structural mechanism for ligand discrimination among hsp90 family members. The structures also identify a putative subdomain that may act as a ligand-responsive switch. The residues of the charged region fold into a disordered loop whose termini are ordered and continue the twisted beta sheet that forms the structural core of the N-domain. This continuation of the beta sheet past the charged domain suggests a structural basis for the association of the N-terminal and middle domains of the full-length chaperone.
GRP94是伴侣蛋白Hsp90在内质网（ER）中的同源物，分别在注定要转运到细胞表面的一部分蛋白质（如Toll样受体2和4以及IgG）的结构成熟或分泌过程中发挥重要作用。GRP94与细胞质Hsp90不同，其ATP结合和水解活性非常弱。GRP94还选择性地结合一系列取代的腺苷类似物。GRP94的N端和相邻带电结构域与N - 乙基羧酰胺腺苷、雷帕霉素和2 - 氯脱氧腺苷形成复合物时，分辨率为1.75 - 2.1 Å的高分辨率晶体结构揭示了hsp90家族成员之间配体识别的结构机制。这些结构还确定了一个可能作为配体响应开关的推定亚结构域。带电区域的残基折叠成一个无序环，其末端是有序的，并延续形成N结构域结构核心的扭曲β折叠片层。β折叠片层越过带电结构域的这种延续为全长伴侣蛋白的N端和中间结构域的关联提供了结构基础。
