Proteolysis triggers self-assembly and unmasks innate immune function of a human α-defensin peptide
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Nolan_Proteolysis triggers.pdf
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Author(s)
Chu, Hiutung
Castillo, Patricia A.
Shen, Bo
Bevins, Charles L.
Chairatana, Phoom
Nolan, Elizabeth Marie
Date Issued
December 2015
Journal
Chemical Science
Publisher
Royal Society of Chemistry (RCS)
Citation
Chairatana, Phoom, Hiutung Chu, Patricia A. Castillo, Bo Shen, Charles L. Bevins, and Elizabeth M. Nolan. “Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a Human α-Defensin Peptide.” Chem. Sci. 7, no. 3 (July 2016): 1738–1752.
Version
Final published version
Abstract
Human α-defensin 6 (HD6) is a unique peptide of the defensin family that provides innate immunity in the intestine by self-assembling to form higher-order oligomers that entrap bacteria and prevent host cell invasion. Here, we report critical steps in the self-assembly pathway of HD6. We demonstrate that HD6 is localized in secretory granules of small intestinal Paneth cells. HD6 is stored in these granules as an 81-residue propeptide (proHD6), and is recovered from ileal lumen as a 32-residue mature peptide. The propeptide neither forms higher-order oligomers, nor agglutinates bacteria, nor prevents Listeria monocytogenes invasion into epithelial cells. The Paneth cell granules also contain the protease trypsin, and trypsin-catalyzed hydrolysis of proHD6 liberates mature HD6, unmasking its latent activities. This work illustrates a remarkable example of how nature utilizes a propeptide strategy to spatially and temporally control peptide self-assembly, and thereby initiates innate immune function in the human intestine.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
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Creative Commons Attribution-NonCommercial 3.0 Unported licence
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DOI of Published Version
https://doi.org/10.1039/c5sc04194e
