Peptidylprolyl isomerase Pin1 directly enhances the DNA binding functions of estrogen receptor α

Prashant Rajbhandari, Mary Szatkowski Ozers, Natalia M. Solodin, Christopher L. Warren, Elaine T. Alarid

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The transcriptional activity of estrogen receptor α (ERα), the key driver of breast cancer proliferation, is enhanced by multiple cellular interactions, including phosphorylation-dependent interaction with Pin1, a proline isomerase, which mediates cistrans isomerization of the N-terminal Ser(P)118-Pro119 in the intrinsically disordered AF1 (activation function 1) domain of ERα. Because both ERα and Pin1 have multiple cellular partners, it is unclear how Pin1 assists in the regulation of ERα transactivation mechanisms and whether the functional effects of Pin1 on ERα signaling are direct or indirect. Here, we tested the specific action of Pin1 on an essential step in ERα transactivation, binding to specific DNA sites. DNA binding analysis demonstrates that stable overexpression of Pin1 increases endogenous ERα DNA binding activity when activated by estrogen but not by tamoxifen or EGF. Increased DNA binding affinity is a direct effect of Pin1 on ERα because it is observed in solution-based assays with purified components. Further, our data indicate that isomerization is required for Pin1-modulation of ERα-DNA interactions. In an unbiased in vitro DNA binding microarray with hundreds of thousands of permutations of ERα-binding elements, Pin1 selectively enhances the binding affinity of ERα to consensus DNA elements. These studies reveal that Pin1 isomerization of phosphorylated ERα can directly regulate the function of the adjacent DNA binding domain, and this interaction is further modulated by ligand binding in the ligand-binding domain, providing evidence for Pin1-dependent allosteric regulation of ERα function.

Original languageEnglish
Pages (from-to)13749-13762
Number of pages14
JournalJournal of Biological Chemistry
Volume290
Issue number22
DOIs
StatePublished - 29 May 2015
Externally publishedYes

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