Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance
Abstract
Estrogen receptor alpha (ERa) is the principle chemotherapeutic target for estrogen dependent breast cancers. Calmodulin (CaM) is an obligatory ERa activator. Moreover, antiestrogens (tamoxifen) bind tightly to CaM, and some therapeutic benefits of antiestrogens for breast cancers are hypothesized to derive from this interaction. The purpose and scope of the research is to define the structural requisites of ERa activation by CaM and the relationship between tamoxifen binding to CaM, CaM oxidation and antiestrogen resistance. We localized a high affinity CaM binding site on ERa (residues 287-311) and a second, low affinity site (241-273). We produced a protein construct for structural studies (residues 286-552) and initiated structural studies of this complex. We determined that a shorter region of ERa (295-311), reported previously to be the CaM binding domain, does not represent the entire domain. We localized and quantified the structural changes that occur in CaM when bound to the high affinity CaM binding domain of ERa, and showed that this CaM binding region of ERa forms a helix when bound to CaM. Localization of the CaM binding site(s) of ERa is critical for understanding the CaM activation process. We also found that oxidation of the methionine residues in CaM abrogates the binding of tamoxifen and hydroxytamoxifen, suggesting oxididative stress contributions to development of antiestrogen resistance.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2008
- Accession Number
- ADA488056
Entities
People
- Jeffrey L. Urbauer
Organizations
- University of Georgia