Radhakrishnan, I. | Search bioRxiv

bioRxiv2023

Prostaglandins as Candidate Ligands for a Per-ARNT-Sim (PAS) Domain of Steroid Receptor Coactivator 1 (SRC1)

Steroid receptor coactivators (SRCs) comprise a family of three paralogous proteins commonly recruited by eukaryotic transcription factors. Each SRC harbors two tandem Per-ARNT-Sim (PAS) domains that are broadly distributed that bind small molecules and regulate interactions. Using computational docking, solution NMR, mass spectrometry, and molecular dynamics simulations, we show that the SRC1 PAS-B domain can bind to certain prostaglandins (PGs) either non-covalently to a surface that overlaps with the site used to engage transcription factors or covalently to a single, specific, conserved cysteine residue next to a solvent accessible hydrophobic pocket. This pocket is in proximity to the canonical transcription factor binding site, but on the opposite side of the domain, suggesting a potential mode of regulating transcriptional activator-coactivator interactions.

biochemistry↗

bioRxiv2021

A Capped Tudor Domain within a Core Subunit of the Sin3L/Rpd3L Histone Deacetylase Complex Binds Nucleic Acids

Chromatin-modifying complexes containing histone deacetylase (HDAC) activities play critical roles in the regulation of gene transcription in eukaryotes. These complexes are thought to lack intrinsic DNA-binding activity, but according to a well-established paradigm, they are recruited via protein-protein interactions by gene-specific transcription factors and post-translational histone modifications to their sites of action on the genome. The mammalian Sin3L/Rpd3L complex, comprising more than a dozen different polypeptides, is an ancient HDAC complex found in diverse eukaryotes. The subunits of this complex harbor conserved domains and motifs of unknown structure and function. Here we show that Sds3, a constitutively associated subunit critical for the proper functioning of the complex, harbors a type of Tudor domain that we designate the capped Tudor domain (CTD). Unlike canonical Tudor domains that bind modified histones, the Sds3 CTD binds to nucleic acids that can form higher-order structures such as G-quadruplexes, and shares similarities with the knotted Tudor domain of the Esa1 histone acetyltransferase (HAT) that was previously shown to bind single-stranded RNA. Our findings expand the range of macromolecules capable of recruiting the Sin3L/Rpd3L complex and draws attention to potentially new roles for this HDAC complex in transcription biology.

biochemistry↗