Dataset Information

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

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 (A?) 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.

SUBMITTER: Solarski M

PROVIDER: S-EPMC6538167 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Solarski Michael M Williams Declan D Mehrabian Mohadeseh M Wang Hansen H Wille Holger H Schmitt-Ulms Gerold G

PloS one 20190528 5

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 biologica ...[more]

PMID: 31136617

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Project description:Accumulation of phosphorylated tau is a key pathological feature of Alzheimer's disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer's disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer's disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer's disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer's disease.

Dataset Information

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

Publications

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

Similar Datasets

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