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Reduction of human defensin 5 affords a high-affinity zinc-chelating peptide.

ABSTRACT: Human defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits three disulfide bonds in the oxidized form (HD5ox). It is abundant in small intestinal Paneth cells, which release HD5 into the intestinal lumen and house a labile Zn(II) store of unknown function. Here, we consider the redox properties of HD5 and report that the reduced form, HD5red, is a metal-ion chelator. HD5 has a midpoint potential of -257 mV at pH 7.0. HD5red utilizes its cysteine residues to coordinate one equivalent of Zn(II) with an apparent Kd1 value in the midpicomolar range. Zn(II) or Cd(II) binding perturbs the oxidative folding pathway of HD5red to HD5ox. Whereas HD5red is highly susceptible to proteolytic degradation, the Zn(II)-bound form displays resistance to hydrolytic breakdown by trypsin and other proteases. The ability of a reduced defensin peptide to coordinate Zn(II) provides a putative mechanism for how these peptides persist in vivo.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3783636 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Reduction of human defensin 5 affords a high-affinity zinc-chelating peptide.

Zhang Yunfei Y Cougnon Fabien B L FB Wanniarachchi Yoshitha A YA Hayden Joshua A JA Nolan Elizabeth M EM

ACS chemical biology 20130710 9

Human defensin 5 (HD5) is a 32-residue cysteine-rich host-defense peptide that exhibits three disulfide bonds in the oxidized form (HD5ox). It is abundant in small intestinal Paneth cells, which release HD5 into the intestinal lumen and house a labile Zn(II) store of unknown function. Here, we consider the redox properties of HD5 and report that the reduced form, HD5red, is a metal-ion chelator. HD5 has a midpoint potential of -257 mV at pH 7.0. HD5red utilizes its cysteine residues to coordinat ...[more]

PMID: 23841778

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Project description:BACKGROUND: Sunflower trypsin inhibitor-1 (SFTI-1) and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are potent protease inhibitors comprising a cyclic backbone. RESULTS: Elucidation of structure-activity relationships for SFTI-1 and MCoTI-II was used to design inhibitors with enhanced inhibitory activity. CONCLUSION: An analog of MCoTI-II is one of the most potent inhibitors of matriptase. SIGNIFICANCE: These results provide a solid basis for the design of selective peptide inhibitors of matriptase with therapeutic potential. The type II transmembrane serine protease matriptase is a key activator of multiple signaling pathways associated with cell proliferation and modification of the extracellular matrix. Deregulated matriptase activity correlates with a number of diseases, including cancer and hence highly selective matriptase inhibitors may have therapeutic potential. The plant-derived cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), is a promising drug scaffold with potent matriptase inhibitory activity. In the current study we have analyzed the structure-activity relationships of SFTI-1 and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II), a structurally divergent trypsin inhibitor from Momordica cochinchinensis that also contains a cyclic backbone. We show that MCoTI-II is a significantly more potent matriptase inhibitor than SFTI-1 and that all alanine mutants of both peptides, generated using positional scanning mutagenesis, have decreased trypsin affinity, whereas several mutations either maintain or result in enhanced matriptase inhibitory activity. These intriguing results were used to design one of the most potent matriptase inhibitors known to date with a 290 pm equilibrium dissociation constant, and provide the first indication on how to modulate affinity for matriptase over trypsin in cyclic peptides. This information might be useful for the design of more selective and therapeutically relevant inhibitors of matriptase.

Dataset Information

Reduction of human defensin 5 affords a high-affinity zinc-chelating peptide.

Publications

Reduction of human defensin 5 affords a high-affinity zinc-chelating peptide.

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