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Chem Sci. 2016 Mar 1;7(3):1738-1752. doi: 10.1039/C5SC04194E. Epub 2015 Dec 10.

Proteolysis Triggers Self-Assembly and Unmasks Innate Immune Function of a Human α-Defensin Peptide.

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Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Department of Microbiology and Immunology, University of California Davis School of Medicine, Davis, CA 95616, USA.
Department of General Internal Medicine and Gastroenterology and Hepatology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Contributed equally


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 high-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.

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