Dataset Information

Human ?-defensin-3 structure motifs that are important in CXCR4 antagonism.

ABSTRACT: Previously, we reported that human ?-defensin (hBD)-3 can both antagonize CXCR4 function on T cells and promote receptor internalization in the absence of activation. In the present study, we explored the important structural elements of hBD-3 that are involved in blocking CXCR4 activation by its natural ligand, stromal-derived factor 1? (SDF-1?; CXCL12). Results from site-directed mutagenesis studies suggest that the ability of hBD-3 to inhibit SDF-1?-CXCR4 interaction, as assayed either by blocking SDF-1 binding to CXCR4 or antagonizing SDF-1-induced Ca(2+) mobilization, is correlated with the presence of hBD-3 cysteine residues, specific surface-distributed cationic residues, and the electrostatic properties and availability of both hBD-3 termini. Specifically, hBD-3 activity against CXCR4 is reduced by: (a) replacing all six cysteines; (b) replacing the cationic residues with acidic ones in the N-terminus and C- terminus; (c) removal of the first 10 N-terminal residues; and (d) replacing the surface-exposed basic residues Lys8, Lys32 and Arg36 with neutral ones. The hBD-3-CXCR4 interaction has potentially wide-ranging implications for HIV-related biology, as well as for a host of CXCR4-dependent activities, including hematopoiesis, neurogenesis, angiogenesis, carcinogenesis, and immune cell trafficking. CXCR4 is highly expressed on T cells, monocytes, and epithelial cells. Therefore, understanding the structure-function relationship between hBD-3 and CXCR4 that accounts for the antagonistic interaction between the two molecules may provide new insights into HIV/highly active antiretroviral therapy-related pathology, as well as novel insights into the interaction between innate and adaptive immunity at mucosal sites.

SUBMITTER: Feng Z

PROVIDER: S-EPMC3831652 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Human β-defensin-3 structure motifs that are important in CXCR4 antagonism.

Feng Zhimin Z Dubyak George R GR Jia Xun X Lubkowski Jacek T JT Weinberg Aaron A

The FEBS journal 20130607 14

Previously, we reported that human β-defensin (hBD)-3 can both antagonize CXCR4 function on T cells and promote receptor internalization in the absence of activation. In the present study, we explored the important structural elements of hBD-3 that are involved in blocking CXCR4 activation by its natural ligand, stromal-derived factor 1α (SDF-1α; CXCL12). Results from site-directed mutagenesis studies suggest that the ability of hBD-3 to inhibit SDF-1α-CXCR4 interaction, as assayed either by blo ...[more]

PMID: 23659571

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Dataset Information

Human ?-defensin-3 structure motifs that are important in CXCR4 antagonism.

Publications

Human β-defensin-3 structure motifs that are important in CXCR4 antagonism.

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