Selective binding of estrogen receptor α to ubiquitin chains

Abstract

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 a (ERa) protein. We have shown that the leucine (L) 429 and alanine (A) 430 ERa 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 ERa to associate with Ub in cell lines. Thus, we evaluated the possibility that one or both ERa Ub binding surfaces could noncovalently interact with other Ub chains. Here, we report that ERa selectively binds to specific Ub chains based on different Ub linkages and that ERa monoubiquitination requires noncovalent ERa: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 ERa functions that could be relevant to ERa-related diseases.

Decoding the Therapeutic Implications of the ERα Stability and Subcellular Distribution in Breast Cancer

“…In addition, UBD or ubiquitin-binding domains have been identified in the LBD of ERα ( L429 and A430 residues), allowing the association of this receptor with ubiquitinated proteins. ERα monoubiquitination and its activity are affected when UBD is mutated ( 78 , 79 ).…”

Proteolysis-targeting chimeras and their implications in breast cancer

“…Since PROTACs are designed to bind to specific targets, sometimes the large size of molecules can affect their bioavailability and solubility. PROTAC bioavailability is also affected by intraperitoneal and subcutaneous administration which are the two current standards of administration; accordingly, new intravenous and oral methods of administration are being investigated [22,[29][30][31].…”

Pathological Maintenance and Evolution of Breast Cancer: The Convergence of Irreversible Biological Actions of ER Alpha

“…Molecular aspects of ERα-mediated transcriptions include allosteric mechanisms related to the intracellular traffics of the receptor and cofactor recruitments [8,9,[45][46][47][48][49][50][51]. These events analyzed in details in Sections 5-7 are briefly described here under to stress their importance to satisfy homeostasis or evolution.…”

“…To this end, ERα is subjected to successive conformtional changes, mainly through phosphorylations, methylations, acetylations, and ubiquitilations [46] and related coactivators recruitments, some of them containing a LxxLL motif operating at the AF-2 site of the receptor [8,9]. These changes occur at least in part on a "hub/platform" [47] localized in front of the ligand binding domain [46,48,49] to facilitate cooperative actions or exchanges between the receptor in its partners according to a well-defined program, a function that would also protect the transcriptional cycle against inappropriate interferences (Section 6). Rapidity of the regulatory "dialog" at this level most likely limits such potential deleterious effects.…”

“…Rapidity of the regulatory "dialog" at this level most likely limits such potential deleterious effects. Subsequent monoubiquitilation through non-covalent interactions with Leu 429 and Ala 330 implicated in signal transductions and Lys 302 and 303 of the exchange hub ("couple monoubiquitilation") favors a cooperation between the AF-1 and AF-2 sites of ERα for the final accomplishment of its transcriptional mission [48]. In this regard, monoubiquitilation distinguishes from polyubiquitilation, which arrests transcription by a proteosomal receptor degradation.…”