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An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides
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An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides
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Journal Article
An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides
2014
Overview
Structure-guided peptide phage display combined with activity-based sorting results in the identification of zymogen activator peptides (ZAPtides) that selectively bind and activate the serine protease–like pro-HGF zymogen to promote Met signaling.
Stimulation of hepatocyte growth factor (HGF) signaling through the Met receptor is an attractive approach for promoting tissue repair and preventing fibrosis. Using structure-guided peptide phage display combined with an activity-based sorting strategy, we engineered allosteric activators of zymogen-like pro-HGF to bypass proteolytic activation and reversibly stimulate pro-HGF signaling through Met. Biochemical, structural and biological data showed that zymogen activator peptides (ZAPtides) potently and selectively bind the activation pocket within the serine protease–like β-chain of pro-HGF and display titratable activation of pro-HGF–dependent Met signaling, leading to cell survival and migration. To further demonstrate the versatility of our ZAPtide platform, we identified allosteric activators for pro–macrophage stimulating protein and a zymogen serine protease, Protein C, which also provides evidence for target selectivity. These studies reveal that ZAPtides use molecular mimicry of the trypsin-like N-terminal insertion mechanism and establish a new paradigm for selective pharmacological activation of plasminogen-related growth factors and zymogen serine proteases.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 13/95
/ 631/45
/ 82/103
/ 82/75
/ 82/83
/ Allosteric Regulation - drug effects
/ Allosteric Site - drug effects
/ Animals
/ Cell Movement - drug effects
/ Cell Survival - drug effects
/ Hepatocyte Growth Factor - chemistry
/ Hepatocyte Growth Factor - genetics
/ Hepatocyte Growth Factor - metabolism
/ Humans
/ Neurons
/ Peptides
/ Peptides - chemical synthesis
/ Protein Precursors - chemistry
/ Protein Precursors - genetics
/ Protein Precursors - metabolism
/ Proto-Oncogene Proteins - chemistry
/ Proto-Oncogene Proteins - genetics
/ Proto-Oncogene Proteins - metabolism
/ Proto-Oncogene Proteins c-met - chemistry
/ Proto-Oncogene Proteins c-met - genetics
/ Proto-Oncogene Proteins c-met - metabolism
