8PXW

Structure of the WW domain tandem of PRPF40A

8PXW の概要

• エントリーDOI: 10.2210/pdb8pxw/pdb
• NMR情報: BMRB: 34839
• 分子名称: Pre-mRNA-processing factor 40 homolog A (1 entity in total)
• 機能のキーワード: dynamic ww domain tandem, proline binding domain, alternative splicing regulation, e complex, splicing
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 11450.69

構造登録者

Martinez-Lumbreras, S.,Sattler, M. (登録日: 2023-07-24, 公開日: 2024-04-03, 最終更新日: 2024-05-22)

主引用文献

Martinez-Lumbreras, S.,Trager, L.K.,Mulorz, M.M.,Payr, M.,Dikaya, V.,Hipp, C.,Konig, J.,Sattler, M.
Intramolecular autoinhibition regulates the selectivity of PRPF40A tandem WW domains for proline-rich motifs.
Nat Commun, 15:3888-3888, 2024

PubMed Abstract: PRPF40A plays an important role in the regulation of pre-mRNA splicing by mediating protein-protein interactions in the early steps of spliceosome assembly. By binding to proteins at the 5´ and 3´ splice sites, PRPF40A promotes spliceosome assembly by bridging the recognition of the splices. The PRPF40A WW domains are expected to recognize proline-rich sequences in SF1 and SF3A1 in the early spliceosome complexes E and A, respectively. Here, we combine NMR, SAXS and ITC to determine the structure of the PRPF40A tandem WW domains in solution and characterize the binding specificity and mechanism for proline-rich motifs recognition. Our structure of the PRPF40A WW tandem in complex with a high-affinity SF1 peptide reveals contributions of both WW domains, which also enables tryptophan sandwiching by two proline residues in the ligand. Unexpectedly, a proline-rich motif in the N-terminal region of PRPF40A mediates intramolecular interactions with the WW tandem. Using NMR, ITC, mutational analysis in vitro, and immunoprecipitation experiments in cells, we show that the intramolecular interaction acts as an autoinhibitory filter for proof-reading of high-affinity proline-rich motifs in bona fide PRPF40A binding partners. We propose that similar autoinhibitory mechanisms are present in most WW tandem-containing proteins to enhance binding selectivity and regulation of WW/proline-rich peptide interaction networks.

PubMed: 38719828
DOI: 10.1038/s41467-024-48004-x

実験手法

SOLUTION NMR