美国凯斯西储大学杨泗春研究组揭示了内源性ERα无序区的序列–结构–功能关系。该研究于2025年1月8日在线发表于国际一流学术期刊《自然》。

研究人员表示，雌激素受体（ER或ERα）是驱动大多数乳腺癌的核激素受体，通常通过在其内源性无序N端转录激活区的丝氨酸118位点的磷酸化来激活。尽管这种修饰使雌激素独立的ER功能得以实现，但其机制仍不清楚，尽管已有针对该区域的激酶抑制剂的临床试验。

通过将小角度X射线散射和核磁共振光谱与功能研究结合，研究人员发现丝氨酸118的磷酸化触发了无序区的意外扩展，并破坏了两个富含芳香族的区域之间特定的疏水聚集。模拟这种破坏的突变能够恢复磷酸化缺失的S118A突变所导致的ER转录活性、靶基因表达和细胞生长。

这些由疏水相互作用驱动的发现超越了电荷模型，并为内在无序蛋白提供了机制性见解，对其他核受体也具有重要意义。这一基本的序列–结构–功能关系促进了人们对内在ER无序的理解，这对开发靶向乳腺癌的治疗方法至关重要。

附：英文原文

Title: The sequence–structure–function relationship of intrinsic ERα disorder

Author: Du, Zhanwen, Wang, Han, Luo, Shuqi, Yun, Zixi, Wu, Chen, Yang, Wangfei, Buck, Matthias, Zheng, Wenwei, Hansen, Alexandar L., Kao, Hung-Ying, Yang, Sichun

Issue&Volume: 2025-01-08

Abstract: The oestrogen receptor (ER or ERα), a nuclear hormone receptor that drives most breast cancer1, is commonly activated by phosphorylation at serine118 within its intrinsically disordered N-terminal transactivation domain2,3. Although this modification enables oestrogen-independent ER function, its mechanism has remained unclear despite ongoing clinical trials of kinase inhibitors targeting this region4,5,6. By integration of small-angle X-ray scattering and nuclear magnetic resonance spectroscopy with functional studies, we show that serine118 phosphorylation triggers an unexpected expansion of the disordered domain and disrupts specific hydrophobic clustering between two aromatic-rich regions. Mutations mimicking this disruption rescue ER transcriptional activity, target-gene expression and cell growth impaired by a phosphorylation-deficient S118A mutation. These findings, driven by hydrophobic interactions, extend beyond electrostatic models and provide mechanistic insights into intrinsically disordered proteins7, with implications for other nuclear receptors8. This fundamental sequence–structure–function relationship advances our understanding of intrinsic ER disorder, crucial for developing targeted breast cancer therapeutics.

DOI: 10.1038/s41586-024-08400-1

Source: https://www.nature.com/articles/s41586-024-08400-1