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The nearly identical paralog, <jats:italic>SMN2<\/jats:italic>, cannot compensate for the loss of <jats:italic>SMN1<\/jats:italic> because exon 7 is aberrantly skipped from most <jats:italic>SMN2<\/jats:italic> transcripts, a process mediated by synergistic activities of Src\u2010associated during mitosis, 68\u2009kDa (Sam68\/KHDRBS1) and heterogeneous nuclear ribonucleoprotein (hnRNP) A1. This results in the production of a truncated, nonfunctional protein that is rapidly degraded. Here, we present several crystal structures of Sam68 RNA\u2010binding domain (RBD). Sam68\u2010RBD forms stable symmetric homodimers by antiparallel association of helices \u03b13 from two monomers. However, the details of domain organization and the dimerization interface differ significantly from previously characterized homologs. We demonstrate that Sam68 and hnRNP A1 can simultaneously bind proximal motifs within the central region of <jats:italic>SMN2<\/jats:italic> (ex7). Furthermore, we show that the RNA\u2010binding pockets of the two proteins are close to each other in their heterodimeric complex and identify contact residues using crosslinking\u2010mass spectrometry. We present a model of the ternary Sam68\u00b7<jats:italic>SMN2<\/jats:italic> (ex7)\u00b7hnRNP A1 complex that reconciles all available information on <jats:italic>SMN1<\/jats:italic>\/<jats:italic>2<\/jats:italic> splicing. Our findings have important implications for the etiology of SMA and open new avenues for the design of novel therapeutics to treat splicing diseases.<\/jats:p>","DOI":"10.1002\/pro.4553","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T06:49:30Z","timestamp":1671778170000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Structure and function analysis of Sam68 and <scp>hnRNP A1<\/scp> synergy in the exclusion of exon 7 from <scp><i>SMN2<\/i><\/scp> transcripts"],"prefix":"10.1002","volume":"32","author":[{"given":"Marta","family":"Nadal","sequence":"first","affiliation":[{"name":"Molecular Bases of Disease Biomedical Research Institute Sant Pau (IIB Sant Pau)  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Anton","sequence":"additional","affiliation":[{"name":"Molecular Bases of Disease Biomedical Research Institute Sant Pau 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Molecular Genetics Hospital Vall d'Hebron  Barcelona Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6618-3204","authenticated-orcid":false,"given":"Pablo","family":"Fuentes\u2010Prior","sequence":"additional","affiliation":[{"name":"Molecular Bases of Disease Biomedical Research Institute Sant Pau (IIB Sant Pau)  Barcelona 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