Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins.
Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins.
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DOI：
10.4049/jimmunol.0900811
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发表时间：
2009-10-15
期刊：
影响因子：
--
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Morales C;Wu S;Yang Y;Hao B;Li Z
哺乳动物热休克蛋白gp96是多种整合素和tlr的专性伴侣，其机制在很大程度上尚不清楚。我们在果蝇中鉴定出gp93与gp96具有高度的序列同源性。然而，以前没有发现gp93的功能。为了确定gp93和gp96是否在功能上保守，我们在gp96缺失的小鼠细胞中表达了gp93。值得注意的是，果蝇gp93能够陪伴多种小鼠gp96客户，包括整合素α4、αL、β2和TLR2和TLR9。这一观察结果使我们通过gp96和gp93之间的密切比较来研究gp96的伴侣功能的结构基础。我们报道，gp96通过Cys138形成分子间二硫键，而gp93由于在同一区域附近缺少半胱氨酸而无法这样做。然而，通过位点定向诱变用A （C138A）取代gp96中的C来消除二硫键的形成并没有损害其伴侣的功能。同样，gp93的伴侣能力也不能通过强迫gp93 N末端之间形成分子间键来提高。我们得出结论，gp93是gp96的果蝇同源物，并且这两个分子的伴侣功能是保守的。此外，gp96 n端二硫键的形成对其功能并不重要，这强调了gp96在客户蛋白折叠中通过非二硫键介导的相互作用进行n端二聚化的重要性。进一步从进化角度对gp96进行研究，将有助于揭示其在分泌通路中对客户蛋白起伴侣作用的详细机制。
Mammalian heat shock protein gp96 is an obligate chaperone for multiple integrins and TLRs, the mechanism of which is largely unknown. We have identified gp93 in Drosophila having high sequence homology to gp96. However, no functions were previously attributed to gp93. To determine whether gp93 and gp96 are functionally conserved, we have expressed gp93 in gp96-deficient mouse cells. Remarkably, the Drosophila gp93 is able to chaperone multiple murine gp96 clients including integrins α4, αL, and β2 and TLR2 and TLR9. This observation has led us to examine the structural basis of the chaperone function of gp96 by a close comparison between gp96 and gp93. We report that whereas gp96 undergoes intermolecular disulfide bond formation via Cys138, gp93 is unable to do so due to the absence of a cysteine near the same region. However, abrogation of disulfide bond formation by substituting C with A (C138A) in gp96 via site-directed mutagenesis did not compromise its chaperone function. Likewise, gp93 chaperone ability could not be improved by forcing intermolecular bond formation between gp93 N termini. We conclude that gp93 is the Drosophila ortholog of gp96 and that the chaperone function of the two molecules is conserved. Moreover, gp96 N-terminal disulfide bond formation is not critical for its function, underscoring the importance of N-terminal dimerization via non-disulfide bond-mediated interactions in client protein folding by gp96. Further study of gp96 from an evolutionary angle shall be informative to uncover the detailed mechanism of its chaperone function of client proteins in the secretory pathway.
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