Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing.
Amino Acid Substitution
Asparagine
/ genetics
Computational Biology
Exons
/ genetics
Glutamic Acid
/ genetics
HEK293 Cells
Humans
Molecular Dynamics Simulation
Muscular Atrophy, Spinal
/ genetics
Nuclear Magnetic Resonance, Biomolecular
Protein Engineering
RNA Recognition Motif
/ genetics
RNA Splice Sites
/ genetics
RNA Splicing
Recombinant Proteins
/ genetics
Serine-Arginine Splicing Factors
/ genetics
Survival of Motor Neuron 1 Protein
/ genetics
Uridine
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
18 01 2021
18 01 2021
Historique:
received:
11
05
2020
accepted:
30
11
2020
entrez:
19
1
2021
pubmed:
20
1
2021
medline:
30
1
2021
Statut:
epublish
Résumé
The human prototypical SR protein SRSF1 is an oncoprotein that contains two RRMs and plays a pivotal role in RNA metabolism. We determined the structure of the RRM1 bound to RNA and found that the domain binds preferentially to a CN motif (N is for any nucleotide). Based on this solution structure, we engineered a protein containing a single glutamate to asparagine mutation (E87N), which gains the ability to bind to uridines and thereby activates SMN exon7 inclusion, a strategy that is used to cure spinal muscular atrophy. Finally, we revealed that the flexible inter-RRM linker of SRSF1 allows RRM1 to bind RNA on both sides of RRM2 binding site. Besides revealing an unexpected bimodal mode of interaction of SRSF1 with RNA, which will be of interest to design new therapeutic strategies, this study brings a new perspective on the mode of action of SRSF1 in cells.
Identifiants
pubmed: 33462199
doi: 10.1038/s41467-020-20481-w
pii: 10.1038/s41467-020-20481-w
pmc: PMC7813835
doi:
Substances chimiques
RNA Splice Sites
0
Recombinant Proteins
0
SMN1 protein, human
0
SRSF1 protein, human
0
Survival of Motor Neuron 1 Protein
0
Serine-Arginine Splicing Factors
170974-22-8
Glutamic Acid
3KX376GY7L
Asparagine
7006-34-0
Uridine
WHI7HQ7H85
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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