The human brain somatostatin interactome: SST binds selectively to P-type family ATPases

Michael Solarski; Declan Williams; Mohadeseh Mehrabian; Hansen Wang; Holger Wille; Gerold Schmitt-Ulms

doi:10.1371/journal.pone.0217392

The human brain somatostatin interactome: SST binds selectively to P-type family ATPases

PLoS One. 2019 May 28;14(5):e0217392. doi: 10.1371/journal.pone.0217392. eCollection 2019.

Authors

Michael Solarski¹, Declan Williams¹, Mohadeseh Mehrabian¹, Hansen Wang¹, Holger Wille^{2

3}, Gerold Schmitt-Ulms^{1

4}

Affiliations

¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Centre, Toronto, Ontario, Canada.
² Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
³ Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada.
⁴ Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Abstract

Somatostatin (SST) is a cyclic peptide that is understood to inhibit the release of hormones and neurotransmitters from a variety of cells by binding to one of five canonical G protein-coupled SST receptors (SSTR1 to SSTR5). Recently, SST was also observed to interact with the amyloid beta (Aβ) peptide and affect its aggregation kinetics, raising the possibility that it may bind other brain proteins. Here we report on an SST interactome analysis that made use of human brain extracts as biological source material and incorporated advanced mass spectrometry workflows for the relative quantitation of SST binding proteins. The analysis revealed SST to predominantly bind several members of the P-type family of ATPases. Subsequent validation experiments confirmed an interaction between SST and the sodium-potassium pump (Na+/K+-ATPase) and identified a tryptophan residue within SST as critical for binding. Functional analyses in three different cell lines indicated that SST might negatively modulate the K+ uptake rate of the Na+/K+-ATPase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides / metabolism
Animals
Brain / metabolism*
Cell Line
HEK293 Cells
Humans
Kinetics
Mice
Nerve Tissue Proteins / metabolism
P-type ATPases / metabolism*
Protein Binding
Protein Interaction Domains and Motifs
Rubidium Radioisotopes / pharmacokinetics
Sodium-Potassium-Exchanging ATPase / metabolism
Somatostatin / metabolism*
Somatostatin-28 / metabolism

Substances

Amyloid beta-Peptides
Nerve Tissue Proteins
Rubidium Radioisotopes
SST protein, human
Somatostatin
Somatostatin-28
P-type ATPases
Sodium-Potassium-Exchanging ATPase

Grants and funding

HoW and GS received funding from the Alberta Prion Research Institute (grant number: 201600028). We are grateful to the Rosiak family for their most generous philanthropic support. The mass spectrometry components of this study were enabled through a major donation by the Irwin family. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.