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Antimicrobial Agents and Chemotherapy, November 2004, p. 4395-4404, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4395-4404.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Platelet Microbicidal Protein 1: Structural Themes of a Multifunctional Antimicrobial Peptide

Nannette Y. Yount,1,2 Kimberly D. Gank,1,2 Yan Qiong Xiong,1,2,3 Arnold S. Bayer,1,2,3 Thomas Pender,4 William H. Welch,4 and Michael R. Yeaman1,2,3*

Division of Infectious Diseases,1 St. John's Cardiovascular Research Center, Harbor-University of California, Los Angeles, Los Angeles Biomedical Research,2 Department of Biochemistry, University of Nevada, Reno, Nevada,4 David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California3

Received 2 March 2004/ Returned for modification 1 April 2004/ Accepted 14 June 2004

Mammalian platelets release platelet microbicidal proteins (PMPs) as components of their antimicrobial armamentarium. The present studies defined the structure of PMP-1 and examined its structure-activity relationships. Amino acid sequencing and mass spectroscopy demonstrated that distinct N-terminal polymorphism variants of PMP-1 isolated from nonstimulated or thrombin-stimulated platelets arise from a single PMP-1 propeptide. Sequence data (NH2-[S]D1DPKE5SEGDL10HCVCV15KTTSL20 . . .) enabled cloning of PMP-1 from bone marrow and characterization of its full-length cDNA. PMP-1 is translated as a 106-amino-acid precursor and is processed to yield 73-residue (8,053 Da) and 72-residue (7,951-Da) variants. Searches with the BLAST program and sequence alignments demonstrated the homology of PMP-1 to members of the mammalian platelet factor 4 (PF-4) family of proteins. On the basis of phylogenetic relatedness, congruent sequence motifs, and predicted three-dimensional structures, PMP-1 shares the greatest homology with human PF-4 (hPF-4). By integration of its structural and antimicrobial properties, these results establish the identity of PMP-1 as a novel rabbit analogue of the microbicidal chemokine (kinocidin) hPF-4. These findings advance the hypothesis that stimuli in the setting of infection prompt platelets to release PF-4-class or related kinocidins, which have structures consistent with their likely multiple roles that bridge molecular and cellular mechanisms of antimicrobial host defense.

* Corresponding author. Mailing address: David Geffen School of Medicine at UCLA, Division of Infectious Diseases, St. John's Cardiovascular Research Center, Research & Education Institute at Harbor-UCLA Medical Center, 1124 West Carson St., RB-2, Torrance, CA 90502. Phone and fax: (310) 782-2016. E-mail: mryeaman{at}ucla.edu.

Antimicrobial Agents and Chemotherapy, November 2004, p. 4395-4404, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4395-4404.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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