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

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.

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