7z1k | pdb_00007z1k
Crystal structure of the SPOC domain of human SHARP (SPEN) in complex with RNA polymerase II CTD heptapeptide phosphorylated on Ser5
Structural highlights
FunctionMINT_HUMAN May serve as a nuclear matrix platform that organizes and integrates transcriptional responses. In osteoblasts, supports transcription activation: synergizes with RUNX2 to enhance FGFR2-mediated activation of the osteocalcin FGF-responsive element (OCFRE) (By similarity). Has also been shown to be an essential corepressor protein, which probably regulates different key pathways such as the Notch pathway. Negative regulator of the Notch pathway via its interaction with RBPSUH, which prevents the association between NOTCH1 and RBPSUH, and therefore suppresses the transactivation activity of Notch signaling. Blocks the differentiation of precursor B-cells into marginal zone B-cells. Probably represses transcription via the recruitment of large complexes containing histone deacetylase proteins. May bind both to DNA and RNA.[1] [2] Publication Abstract from PubMedThe heptad repeats of the C-terminal domain (CTD) of RNA polymerase II (Pol II) are extensively modified throughout the transcription cycle. The CTD coordinates RNA synthesis and processing by recruiting transcription regulators as well as RNA capping, splicing and 3'end processing factors. The SPOC domain of PHF3 was recently identified as a CTD reader domain specifically binding to phosphorylated serine-2 residues in adjacent CTD repeats. Here, we establish the SPOC domains of the human proteins DIDO, SHARP (also known as SPEN) and RBM15 as phosphoserine binding modules that can act as CTD readers but also recognize other phosphorylated binding partners. We report the crystal structure of SHARP SPOC in complex with CTD and identify the molecular determinants for its specific binding to phosphorylated serine-5. PHF3 and DIDO SPOC domains preferentially interact with the Pol II elongation complex, while RBM15 and SHARP SPOC domains engage with writers and readers of m(6)A, the most abundant RNA modification. RBM15 positively regulates m(6)A levels and mRNA stability in a SPOC-dependent manner, while SHARP SPOC is essential for its localization to inactive X-chromosomes. Our findings suggest that the SPOC domain is a major interface between the transcription machinery and regulators of transcription and co-transcriptional processes. The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators.,Appel LM, Franke V, Benedum J, Grishkovskaya I, Strobl X, Polyansky A, Ammann G, Platzer S, Neudolt A, Wunder A, Walch L, Kaiser S, Zagrovic B, Djinovic-Carugo K, Akalin A, Slade D Nat Commun. 2023 Jan 11;14(1):166. doi: 10.1038/s41467-023-35853-1. PMID:36631525[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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