Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Department of Urology, SUNY Upstate Medical University, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
Cell Rep. 2022 Jul 12;40(2):111039. doi: 10.1016/j.celrep.2022.111039.
Heat shock protein-90 (Hsp90) chaperone machinery is involved in the stability and activity of its client proteins. The chaperone function of Hsp90 is regulated by co-chaperones and post-translational modifications. Although structural evidence exists for Hsp90 interaction with clients, our understanding of the impact of Hsp90 chaperone function toward client activity in cells remains elusive. Here, we dissect the impact of recently identified higher eukaryotic co-chaperones, FNIP1/2 (FNIPs) and Tsc1, toward Hsp90 client activity. Our data show that Tsc1 and FNIP2 form mutually exclusive complexes with FNIP1, and that unlike Tsc1, FNIP1/2 interact with the catalytic residue of Hsp90. Functionally, these co-chaperone complexes increase the affinity of the steroid hormone receptors glucocorticoid receptor and estrogen receptor to their ligands in vivo. We provide a model for the responsiveness of the steroid hormone receptor activation upon ligand binding as a consequence of their association with specific Hsp90:co-chaperone subpopulations.
热休克蛋白 90（Hsp90）伴侣蛋白机器参与其客户蛋白的稳定性和活性。Hsp90 的伴侣功能受共伴侣和翻译后修饰调节。尽管存在 Hsp90 与客户相互作用的结构证据，但我们对 Hsp90 伴侣功能对细胞中客户活性的影响仍不清楚。在这里，我们剖析了最近鉴定的高等真核共伴侣 FNIP1/2（FNIPs）和 Tsc1 对 Hsp90 客户活性的影响。我们的数据表明，Tsc1 和 FNIP2 与 FNIP1 形成相互排斥的复合物，与 Tsc1 不同，FNIP1/2 与 Hsp90 的催化残基相互作用。功能上，这些共伴侣复合物增加了甾体激素受体糖皮质激素受体和雌激素受体与它们在体内配体的亲和力。我们提供了一个模型，说明甾体激素受体激活对配体结合的响应性，这是由于它们与特定的 Hsp90：共伴侣亚群的关联。
