A Single Amino Acid Residue Regulates PTEN-Binding and Stability of the Spinal Muscular Atrophy Protein SMN.
Amino Acid Sequence
Amino Acids
/ metabolism
Animals
Caenorhabditis elegans
Cell Line, Tumor
Cell Nucleus
/ metabolism
Gene Knockdown Techniques
Humans
Mice
Mutant Proteins
/ chemistry
PTEN Phosphohydrolase
/ metabolism
Phosphorylation
Phosphoserine
/ metabolism
Proteasome Endopeptidase Complex
/ metabolism
Protein Binding
Protein Stability
Proteolysis
Structure-Activity Relationship
Survival of Motor Neuron 1 Protein
/ chemistry
PTEN
SMN
mass spectrometry
phosphorylation
spinal muscular atrophy
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
03 11 2020
03 11 2020
Historique:
received:
02
06
2020
revised:
23
10
2020
accepted:
27
10
2020
entrez:
6
11
2020
pubmed:
7
11
2020
medline:
16
6
2021
Statut:
epublish
Résumé
Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by decreased levels of the survival of motoneuron (SMN) protein. Post-translational mechanisms for regulation of its stability are still elusive. Thus, we aimed to identify regulatory phosphorylation sites that modulate function and stability. Our results show that SMN residues S290 and S292 are phosphorylated, of which SMN pS290 has a detrimental effect on protein stability and nuclear localization. Furthermore, we propose that phosphatase and tensin homolog (PTEN), a novel phosphatase for SMN, counteracts this effect. In light of recent advancements in SMA therapies, a significant need for additional approaches has become apparent. Our study demonstrates S290 as a novel molecular target site to increase the stability of SMN. Characterization of relevant kinases and phosphatases provides not only a new understanding of SMN function, but also constitutes a novel strategy for combinatorial therapeutic approaches to increase the level of SMN in SMA.
Identifiants
pubmed: 33153033
pii: cells9112405
doi: 10.3390/cells9112405
pmc: PMC7692393
pii:
doi:
Substances chimiques
Amino Acids
0
Mutant Proteins
0
SMN1 protein, human
0
Survival of Motor Neuron 1 Protein
0
Phosphoserine
17885-08-4
PTEN Phosphohydrolase
EC 3.1.3.67
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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