Selective binding of estrogen receptor α to ubiquitin chains.

Ubiquitin (Ub)-binding domains (UBDs) noncovalently contact the Ub modification on binding partners. Ub possesses seven lysine (K) residues (i.e., K6, K11, K27, K29, K33, K48, and K63) that can be used to form different chains based on different Ub linkage types (e.g., monoubiquitination/polyubiquitination). Thus, different Ub-based signals exist and are decoded by UBDs. Recently, we have reported the existence of two Ub binding surfaces located within the estrogen receptor α (ERα) protein. We have shown that the leucine (L) 429 and alanine (A) 430 ERα residues direct noncovalent receptor binding to K63-based Ub chains in vitro. However, mutation of L429 and A430 residues did not completely abolish the ability of ERα to associate with Ub in cell lines. Thus, we evaluated the possibility that one or both ERα Ub binding surfaces could non-covalently interact with other Ub chains. Here, we report that ERα selectively binds to specific Ub chains based on different Ub linkages and that ERα monoubiquitination requires non-covalent ERα:Ub binding. Considering the importance of the UBD:Ub interaction in the initiation and progression of many diseases (e.g., cancer), our data provide novel insights into ERα functions that could be relevant to ERα-related diseases. © 2016 IUBMB Life, 68(7):569-577, 2016.