Biology subjects

Abella, M.

Publications and source records attributed to Abella, M..

4 recordsLinked to original sources

bioRxiv2025

Bile acids target an exposed cavity in the glucocorticoid receptor modulating receptor self-assembly, chromatin binding and transcriptional activity

The glucocorticoid receptor (GR) is an essential transcription factor that controls metabolism and homeostasis. Glucocorticoids (GCs) activate the GR upon occupying the internal ligand-binding pocket (LBP) of its ligand-binding domain (GR-LBD), which has been the focus of most previous structure-function studies. Synthetic GCs such as dexamethasone are widely used to treat inflammatory diseases, but their chronic use results in major side effects, whose molecular underpinnings remain unresolved. Here we present a thorough analysis of the topography of GR-LBD and its ability to bind small-molecule compounds, especially cholesterol derivatives. We show that one important class of steroids, bile acids, bind to previously unidentified and highly conserved, surface-exposed cavities on GR-LBD. We show that bile acids affect GR turnover and self-assembly in living cells, modulating receptor transcriptional activity. These findings reveal a previously unrecognized mechanism of GR regulation, with implications for the design of GCs with novel mechanisms of action. TeaserBile acids modulate the activity of the glucocorticoid receptor upon binding to an exposed allosteric pocket thereby influencing transcriptional regulation and receptor self-assembly in living cells.

molecular biology↗

bioRxiv2024

The multimerization pathway of the glucocorticoid receptor

The glucocorticoid receptor (GR) is a leading drug target due to its anti-inflammatory and immunosuppressive roles. The functional oligomeric conformation of full-length GR (FL-GR), which is key for its biological activity, remains disputed. Here we present a new crystal structure of agonist-bound GR ligand-binding domain (GR-LBD) comprising eight copies of a non-canonical dimer. The biological relevance of this dimer for receptor multimerization in living cells has been verified by studying single-and double-point mutants of FL-GR in fluorescence microscopy (Number & Brightness) and transcriptomic analysis. Self-association of this GR-LBD basic dimer in two mutually exclusive assemblies reveals clues for FL-GR multimerization and activity in cells. We propose a model for the structure of multidomain GR based on our new data and suggest a detailed oligomerization pathway. This model reconciles all currently available structural and functional information and provides a more comprehensive understanding of the rare glucocorticoid resistance disorder (Chrousos syndrome).

biochemistry↗

bioRxiv2021

The multivalency of the glucocorticoid receptor ligand-binding domain explains its manifold physiological activities

The glucocorticoid receptor (GR) is a ubiquitously expressed transcription factor that controls metabolic and homeostatic processes essential for life. Although numerous crystal structures of the GR ligand-binding domain (GR-LBD) have been reported, the functional oligomeric state of the full-length receptor, which is essential for its transcriptional activity, remains disputed. Here we present five new crystal structures of agonist-bound GR-LBD, along with a thorough analysis of previous structural work. Biologically relevant homodimers were identified by studying a battery of GR point mutants including crosslinking assays in solution and quantitative fluorescence microscopy in living cells. Our results highlight the relevance of non-canonical dimerization modes for GR, especially of contacts made by loop L1-3 residues such as Tyr545. Our work unveils likely pathophysiologically relevant quaternary assemblies of the nuclear receptor with important implications for glucocorticoid action and drug design.

biochemistry↗

bioRxiv2020

Structure of the endocytic adaptor complex reveals the basis for efficient membrane anchoring during clathrin-mediated endocytosis

During clathrin-mediated endocytosis, a complex and dynamic network of protein-membrane interactions cooperate to achieve membrane invagination. Throughout this process, middle coat adaptors, Sla2 and Ent1, must remain attached to the plasma membrane to transmit force from the actin cytoskeleton required for successful membrane invagination. Here, we present a cryoEM structure of a 16-mer complex of membrane binding domains from Sla2 and Ent1 that anchors to the plasma membrane. Detailed mutagenesis in vitro and in vivo of the tetramer interfaces delineate the key interactions for complex formation and deficient cell growth phenotypes demonstrate the biological relevance of these interactions. Finally, time-resolved experiments in solution suggest that adaptors have evolved to achieve a fast subsecond timescale assembly in the presence of PIP2. Together, these findings provide a molecular understanding of an essential piece for the molecular puzzle of clathrin-coated sites.

biophysics↗