Maciejewski Andrzej, Prado Marco A, Choy Wing-Yiu
Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
Biomol NMR Assign. 2013 Oct;7(2):305-10. doi: 10.1007/s12104-012-9433-7. Epub 2012 Oct 16.
Hop/STI1 (Hsp-organizing protein/stress-induced-phosphoprotein 1) is a molecular co-chaperone, which coordinates Hsp70 and Hsp90 activity during client protein folding through interactions with its TPR1 and TPR2A domains. Hsp90 substrates include a diverse set of proteins, many of which have been implicated in tumorigenesis. Over-expression of Hsp90 in cancer cells stabilizes mutant oncoproteins promoting cancer cell survival. Disruption of Hsp90 and its co-chaperone machinery has become a promising strategy for the treatment of cancer. STI1 has also been described as a neurotrophic signaling molecule through its interactions with the prion protein (PrP(C)). Here, we report the (1)H, (13)C and (15)N backbone assignments of the TPR1 and TPR2A domains of mouse STI1, which interact with Hsp70 and Hsp90, respectively. (1)H-(15)N HSQC spectra of TPR2A domain in the presence of a peptide encoding the C-terminal Hsp90 binding site revealed significant chemical shift changes indicating complex formation. These results will facilitate the screening of potential molecules that inhibit STI1 complex formation with Hsp70 and/or Hsp90 for the treatment of cancer and detailed structural studies of the STI1-PrP(C) complex.
Hop/STI1（热休克蛋白组织蛋白/应激诱导磷蛋白1）是一种分子伴侣协同蛋白，它在底物蛋白折叠过程中，通过其TPR1和TPR2A结构域的相互作用来协调热休克蛋白70（Hsp70）和热休克蛋白90（Hsp90）的活性。Hsp90的底物包括多种蛋白质，其中许多与肿瘤发生有关。癌细胞中Hsp90的过表达可稳定促进癌细胞存活的突变癌蛋白。破坏Hsp90及其伴侣蛋白机制已成为一种有前景的癌症治疗策略。STI1也被描述为一种神经营养信号分子，通过其与朊病毒蛋白（PrP(C)）的相互作用发挥作用。在此，我们报告了小鼠STI1的TPR1和TPR2A结构域的（1）H、（13）C和（15）N主链归属，这两个结构域分别与Hsp70和Hsp90相互作用。在存在编码C末端Hsp90结合位点的肽的情况下，TPR2A结构域的（1）H-（15）N HSQC谱显示出显著的化学位移变化，表明形成了复合物。这些结果将有助于筛选抑制STI1与Hsp70和/或Hsp90形成复合物以治疗癌症的潜在分子，以及对STI1-PrP(C)复合物进行详细的结构研究。
