A single amino acid residue regulates PTEN-binding and stability of the Spinal Muscular Atrophy protein SMN

Rademacher, Sebastian; Detering, Nora  T.; Schüning, Tobias; Lindner, Robert; Santonicola, Pamela; Wefel, Inga-Maria; Dehus, Janina; Walter, Lisa M.; Brinkmann, Hella; Niewienda, Agathe; Janek, Katharina; Varela, Miguel A.; Bowerman, Melissa; Di Schiavi, Elia; Claus, Peter

doi:10.3390/cells9112405

A single amino acid residue regulates PTEN-binding and stability of the Spinal Muscular Atrophy protein SMN

Rademacher, Sebastian; Detering, Nora T.; Schüning, Tobias; Lindner, Robert; Santonicola, Pamela; Wefel, Inga-Maria; Dehus, Janina; Walter, Lisa M.; Brinkmann, Hella; Niewienda, Agathe; Janek, Katharina; Varela, Miguel A.; Bowerman, Melissa; Di Schiavi, Elia; Claus, Peter

Authors

Sebastian Rademacher

Nora T. Detering

Tobias Schüning

Robert Lindner

Pamela Santonicola

Inga-Maria Wefel

Janina Dehus

Lisa M. Walter

Hella Brinkmann

Agathe Niewienda

Katharina Janek

Miguel A. Varela

Melissa Bowerman m.bowerman@keele.ac.uk

Elia Di Schiavi

Peter Claus

Abstract

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.

Journal Article Type	Article
Acceptance Date	Oct 27, 2020
Online Publication Date	Nov 3, 2020
Publication Date	Nov 3, 2020
Publicly Available Date	Jun 26, 2023
Journal	Cells
Publisher	MDPI
Peer Reviewed	Peer Reviewed
Volume	9
Issue	11
Article Number	2405
DOI	https://doi.org/10.3390/cells9112405
Keywords	mass spectrometry; phosphorylation; PTEN; SMN; spinal muscular atrophy
Publisher URL	https://www.mdpi.com/2073-4409/9/11/2405