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A toolkit for studying cell surface shedding of diverse transmembrane receptors.

ABSTRACT: Proteolysis of transmembrane receptors is a critical cellular communication mechanism dysregulated in disease, yet decoding proteolytic regulation mechanisms of hundreds of shed receptors is hindered by difficulties controlling stimuli and unknown fates of cleavage products. Notch proteolytic regulation is a notable exception, where intercellular forces drive exposure of a cryptic protease site within a juxtamembrane proteolytic switch domain to activate transcriptional programs. We created a Synthetic Notch Assay for Proteolytic Switches (SNAPS) that exploits the modularity and unequivocal input/response of Notch proteolysis to screen surface receptors for other putative proteolytic switches. We identify several new proteolytic switches among receptors with structural homology to Notch. We demonstrate SNAPS can detect shedding in chimeras of diverse cell surface receptors, leading to new, testable hypotheses. Finally, we establish the assay can be used to measure modulation of proteolysis by potential therapeutics and offer new mechanistic insights into how DECMA-1 disrupts cell adhesion.

SUBMITTER: Hayward AN

PROVIDER: S-EPMC6586460 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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A toolkit for studying cell surface shedding of diverse transmembrane receptors.

Hayward Amanda N AN Aird Eric J EJ Gordon Wendy R WR

eLife 20190607

Proteolysis of transmembrane receptors is a critical cellular communication mechanism dysregulated in disease, yet decoding proteolytic regulation mechanisms of hundreds of shed receptors is hindered by difficulties controlling stimuli and unknown fates of cleavage products. Notch proteolytic regulation is a notable exception, where intercellular forces drive exposure of a cryptic protease site within a juxtamembrane proteolytic switch domain to activate transcriptional programs. We created a Sy ...[more]

PMID: 31172946

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Dataset Information

A toolkit for studying cell surface shedding of diverse transmembrane receptors.

Publications

A toolkit for studying cell surface shedding of diverse transmembrane receptors.

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