Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts.

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Tytuł:: Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts.
Autorzy:: Nadal M; Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
Anton R; Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
Dorca-Arévalo J; Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
Estébanez-Perpiñá E; Structural Biology of Nuclear Receptors, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona, Spain.
Tizzano EF; Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.; Department of Clinical and Molecular Genetics, Hospital Vall d'Hebron, Barcelona, Spain.
Fuentes-Prior P; Molecular Bases of Disease, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
Źródło:: Protein science : a publication of the Protein Society [Protein Sci] 2023 Apr; Vol. 32 (4), pp. e4553.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2001- : Woodbury, NY : Cold Spring Harbor Laboratory Press
Original Publication: New York, N.Y. : Cambridge University Press, c1992-
MeSH Terms:: Neurodegenerative Diseases*/genetics
Muscular Atrophy, Spinal*/genetics
Muscular Atrophy, Spinal*/metabolism
Humans ; Heterogeneous Nuclear Ribonucleoprotein A1/genetics ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Exons/genetics ; RNA Splicing ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Adaptor Proteins, Signal Transducing/genetics ; Survival of Motor Neuron 2 Protein/genetics ; Survival of Motor Neuron 2 Protein/metabolism
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Contributed Indexing:: Keywords: RNA binding proteins; STAR family members; Sam68; alternative splicing; hnRNP A1; homodimer; protein-RNA interactions; spinal muscular atrophy; x-ray crystal structure
Substance Nomenclature:: 0 (Heterogeneous Nuclear Ribonucleoprotein A1)
0 (RNA-Binding Proteins)
0 (KHDRBS1 protein, human)
0 (DNA-Binding Proteins)
0 (Adaptor Proteins, Signal Transducing)
0 (SMN2 protein, human)
0 (Survival of Motor Neuron 2 Protein)
Entry Date(s):: Date Created: 20221223 Date Completed: 20230403 Latest Revision: 20240402
Update Code:: 20240402
PubMed Central ID:: PMC10031812
DOI:: 10.1002/pro.4553
PMID:: 36560896
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Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the absence of a functional copy of the Survival of Motor Neuron 1 gene (SMN1). The nearly identical paralog, SMN2, cannot compensate for the loss of SMN1 because exon 7 is aberrantly skipped from most SMN2 transcripts, a process mediated by synergistic activities of Src-associated during mitosis, 68 kDa (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-binding domain (RBD). Sam68-RBD forms stable symmetric homodimers by antiparallel association of helices α3 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 SMN2 (ex7). Furthermore, we show that the RNA-binding pockets of the two proteins are close to each other in their heterodimeric complex and identify contact residues using crosslinking-mass spectrometry. We present a model of the ternary Sam68·SMN2 (ex7)·hnRNP A1 complex that reconciles all available information on SMN1/2 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.
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