Structural Basis for the Interaction of Human β-Defensin 6 and Its Putative Chemokine Receptor CCR2 and Breast Cancer Microvesicles
Human β-defensins (hBDs) are believed to function as alarm molecules that stimulate the adaptive immune system when a threat is present. In addition to its antimicrobial activity, defensins present other activities such as chemoattraction of a range of different cell types to the sites of inflammati...
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Published in: | Journal of molecular biology Vol. 425; no. 22; pp. 4479 - 4495 |
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Main Authors: | , , , , , , |
Format: | Journal Article |
Language: | English |
Published: |
England
Elsevier Ltd
15-11-2013
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Subjects: | |
Online Access: | Get full text |
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Summary: | Human β-defensins (hBDs) are believed to function as alarm molecules that stimulate the adaptive immune system when a threat is present. In addition to its antimicrobial activity, defensins present other activities such as chemoattraction of a range of different cell types to the sites of inflammation. We have solved the structure of the hBD6 by NMR spectroscopy that contains a conserved β-defensin domain followed by an extended C-terminus. We use NMR to monitor the interaction of hBD6 with microvesicles shed by breast cancer cell lines and with peptides derived from the extracellular domain of CC chemokine receptor 2 (Nt-CCR2) possessing or not possessing sulfation on Tyr26 and Tyr28. The NMR-derived model of the hBD6/CCR2 complex reveals a contiguous binding surface on hBD6, which comprises amino acid residues of the α-helix and β2–β3 loop. The microvesicle binding surface partially overlaps with the chemokine receptor interface. NMR spin relaxation suggests that free hBD6 and the hBD6/CCR2 complex exhibit microsecond-to-millisecond conformational dynamics encompassing the CCR2 binding site, which might facilitate selection of the molecular configuration optimal for binding. These data offer new insights into the structure–function relation of the hBD6–CCR2 interaction, which is a promising target for the design of novel anticancer agents.
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•hBD6 displays a cysteine-stabilized fold linked to an unstructured C-terminal region.•Interactions of hbD1 and hbD6 with microvesicles shed by breast cancer cell lines were studied by NMR.•Direct interaction of the hBD6 with the CCR2 sulfopeptide is presented. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-2836 1089-8638 |
DOI: | 10.1016/j.jmb.2013.08.001 |