A Single Amino Acid Residue Regulates PTEN-Binding and Stability of the Spinal Muscular Atrophy Protein SMN
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,
Elia Di Schiavi,
Peter Claus
Affiliations
Sebastian Rademacher
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Nora T. Detering
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Tobias Schüning
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Robert Lindner
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Pamela Santonicola
Institute of Biosciences and Bioresources, National Research Council of Italy, 80131 Naples, Italy
Inga-Maria Wefel
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Janina Dehus
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Lisa M. Walter
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Hella Brinkmann
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
Agathe Niewienda
Shared Facility for Mass Spectrometry, Institute of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Katharina Janek
Shared Facility for Mass Spectrometry, Institute of Biochemistry, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany
Miguel A. Varela
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Melissa Bowerman
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
Elia Di Schiavi
Institute of Biosciences and Bioresources, National Research Council of Italy, 80131 Naples, Italy
Peter Claus
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, 30625 Hannover, Germany
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.
