PXD033055

PXD033055 is an original dataset announced via ProteomeXchange.

Title	The molecular bases of spinal muscular atrophy
Description	Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the absence of a functional 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 Sam68/KHDR1 and hnRNP A1. This results in the production of a truncated, non-functional 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 bind proximal but distinct motifs within the central region of SMN2(ex7). Our findings have important implications for the etiology of SMA and open new avenues for the design of novel therapeutics to treat splicing diseases.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:41:32.489.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD033055
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Marta Vilaseca
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-04-07 03:11:18	ID requested
1	2024-05-22 23:42:23	announced
⏵ 2	2024-10-22 06:41:35	announced	2024-10-22: Updated project metadata.

Nadal M, Anton R, Dorca-Ar, é, valo J, Est, é, banez-Perpi, ñ, á E, Tizzano EF, Fuentes-Prior P, Structure and function analysis of Sam68 and hnRNP A1 synergy in the exclusion of exon 7 from SMN2 transcripts. Protein Sci, 32(4):e4553(2023) [pubmed]

10.6019/PXD033055;

10.1002/pro.4553;

submitter keyword: Biological sciences/Molecular biology/RNA metabolism/Alternative splicing Biological sciences/Structural biology/X-ray crystallography Health sciences/Diseases/Neurological disorders/Motor neuron disease

Mireia Diaz
contact affiliation	Mass Spectometry and Protemics Core Facility, Institute for Research in Biomedicine
contact email	mireia.diaz@irbbarcelona.org
lab head
Marta Vilaseca
contact affiliation	Mass Spectrometry & Proteomics Core Facility (MSPCF) Institute for Research in Biomedicine (IRB Barcelona) Barcelona Institute of Science and Technology (BIST) C/ Baldiri Reixac, 10-12 08028 Barcelona - Spain
contact email	masspe@irbbarcelona.org
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/05/PXD033055

PRIDE project URI

• PRIDE
  1. PXD033055
     1. Label: PRIDE project
     2. Name: The molecular bases of spinal muscular atrophy