The ER Chaperones BiP and Grp94 Regulate the Formation of Insulin-Like Growth Factor 2 (IGF2) Oligomers.
The ER Chaperones BiP and Grp94 Regulate the Formation of Insulin-Like Growth Factor 2 (IGF2) Oligomers.
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DOI：
10.1016/j.jmb.2021.166963
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发表时间：
2021-06-25
影响因子：
5.6
通讯作者：
Street TO
中科院分区：
文献类型：
--
作者：
Jin Y;Kotler JLM;Wang S;Huang B;Halpin JC;Street TO
虽然胞质Hsp 90分子伴侣已被广泛研究，但对ER Hsp 90分子伴侣Grp 94如何识别客户端并影响客户端折叠知之甚少。在这里，我们研究如何Grp 94和ER Hsp 70 paramount，BiP，影响胰岛素样生长因子2（IGF 2），一个既定的客户蛋白Grp 94的折叠。ProIGF 2由二硫键结合的胰岛素样激素和C-末端E-肽组成，所述E-肽具有固有无序区域的序列特征。BiP和Grp 94对折叠的影响最小，因此两种分子伴侣减缓proIGF 2折叠，并且基本上不改变二硫键结合的折叠中间体，这表明BiP和Grp 94可能具有与proIGF 2折叠无关的额外影响。事实上，我们意外地发现E肽区允许proIGF 2形成动态寡聚体。ProIGF 2寡聚体可以从能够交换单体的动态状态转变为不可逆的聚集状态，为BiP和Grp 94在调节proIGF 2寡聚化中提供了合理的作用。与对折叠的适度影响相反，BiP和Grp 94对proIGF 2寡聚化具有更强的影响，并且这些分子伴侣发挥抵消作用。BiP抑制proIGF 2寡聚化，而Grp 94可以以核苷酸依赖性方式增强proIGF 2寡聚化。我们建议BiP和Grp 94调节proIGF 2寡聚体的组装和动态行为，尽管proIGF 2寡聚化的生物学作用尚不清楚。
While cytosolic Hsp90 chaperones have been extensively studied, less is known about how the ER Hsp90 paralog Grp94 recognizes clients and influences client folding. Here, we examine how Grp94 and the ER Hsp70 paralog, BiP, influence the folding of insulin-like growth factor 2 (IGF2), an established client protein of Grp94. ProIGF2 is composed of a disulfide-bonded insulin-like hormone and a C-terminal E-peptide that has sequence characteristics of an intrinsically disordered region. BiP and Grp94 have a minimal influence on folding whereby both chaperones slow proIGF2 folding and do not substantially alter the disulfide-bonded folding intermediates, suggesting that BiP and Grp94 may have an additional influence unrelated to proIGF2 folding. Indeed, we made the unexpected discovery that the E-peptide region allows proIGF2 to form dynamic oligomers. ProIGF2 oligomers can transition from a dynamic state that is capable of exchanging monomers to an irreversibly aggregated state, providing a plausible role for BiP and Grp94 in regulating proIGF2 oligomerization. In contrast to the modest influence on folding, BiP and Grp94 have a stronger influence on proIGF2 oligomerization and these chaperones exert counteracting effects. BiP suppresses proIGF2 oligomerization while Grp94 can enhance proIGF2 oligomerization in a nucleotide-dependent manner. We propose that BiP and Grp94 regulate the assembly and dynamic behavior of proIGF2 oligomers, although the biological role of proIGF2 oligomerization is not yet known.
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影响因子：
5.6
作者：
Daturpalli, Soumya;Waudby, Christopher A.;Jackson, Sophie E.
通讯作者：
Jackson, Sophie E.
HSP90-TAU复合物揭示了伴侣作用特异性的分子基础。
影响因子：
64.5
作者：
Karagöz GE;Duarte AM;Akoury E;Ippel H;Biernat J;Morán Luengo T;Radli M;Didenko T;Nordhues BA;Veprintsev DB;Dickey CA;Mandelkow E;Zweckstetter M;Boelens R;Madl T;Rüdiger SG
通讯作者：
Rüdiger SG
影响因子：
16
作者：
Kityk, Roman;Kopp, Juergen;Mayer, Matthias P.
通讯作者：
Mayer, Matthias P.
影响因子：
2.9
作者：
Chang, Jui-Yoa
通讯作者：
Chang, Jui-Yoa
影响因子：
8
作者：
Arakawa, Akihiko;Handa, Noriko;Yokoyama, Shigeyuki
通讯作者：
Yokoyama, Shigeyuki