title: Human β-defensin-3 structure motifs that are important in CXCR4 antagonism.
abstract: 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 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.
authors: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106-4905, USA.
authors: Zhimin
authors: Z
authors: Feng
authors: George R
authors: GR
authors: Dubyak
authors: Xun
authors: X
authors: Jia
authors: Jacek T
authors: JT
authors: Lubkowski
authors: Aaron
authors: A
authors: Weinberg
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001667:Binding, Competitive; D002460:Cell Line; D054377:Chemokine CXCL12 / Q000378:metabolism; D003553:Cystine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D013499:Surface Properties; D023083:beta-Defensins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; C422950:DEFB103A protein, human; D019718:Receptors, CXCR4; D023083:beta-Defensins; D003553:Cystine
keywords: CXCR4; antagonism; defensin; human β-defensin-3; structure
references: J Pathol. 2008 Jul;215(3):211-3
references: 18523970
references: Nature. 1997 Jun 26;387(6636):861
references: 9202117
references: Science. 2010 Nov 19;330(6007):1066-71
references: 20929726
references: Glia. 2003 Apr 15;42(2):139-48
references: 12655598
references: Biophys J. 2003 Jan;84(1):171-84
references: 12524273
references: J Biol Chem. 2009 Dec 11;284(50):35240-50
references: 19837984
references: J Immunol. 2010 Jun 15;184(12):6688-94
references: 20483750
references: Periodontol 2000. 2010 Oct;54(1):195-206
references: 20712640
references: Acta Pharmacol Sin. 2004 Feb;25(2):152-60
references: 14769202
references: J Immunol. 2006 Jul 15;177(2):782-6
references: 16818731
references: J Mol Histol. 2004 Mar;35(3):233-45
references: 15339043
references: PLoS One. 2010 Jun 08;5(6):e10993
references: 20544025
references: Oral Oncol. 2009 Aug;45(8):696-702
references: 19097930
references: AIDS. 2003 Nov 7;17(16):F39-48
references: 14571200
references: Eur Cytokine Netw. 2004 Jul-Sep;15(3):177-88
references: 15542441
references: J Biol Chem. 2001 Feb 23;276(8):5707-13
references: 11085990
references: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18631-5
references: 18006661
references: Nature. 1998 Jun 11;393(6685):524-5
references: 9634228
references: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8880-5
references: 12840147