Glycation ligand binding motif in lactoferrin. Implications in diabetic infection.
Lactoferrin and lysozyme are two important, naturally occurring antibacterial proteins found in saliva, nasal secretions, milk, mucus, serum and in the lysosomes of neutrophils and macrophages. Both proteins bind specifically to glucose-modified proteins bearing advanced glycation endproducts (AGEs). Exposure to AGE-modified proteins blocks the bacterial agglutination and bacterial killing activities of lactoferrin and also inhibits the bactericidal and enzymatic activity of lysozyme. Peptide mapping by AGE ligand blot revealed two AGE-binding domains in lactoferrin, and a single AGE-binding domain in lysozyme. None of these AGE-binding domains displayed any significant homology in their primary sequences; however, a common 17-18 amino acid cysteine loop motif (CX15-16C) was identified among them, which we named an ABCD motif (AGE-Binding Cysteine-bounded Domain). Similar domains are also present in other antimicrobial proteins such as defesins. Hydrophilicity analysis indicated that each of these ABCD loops is markedly hydrophilic. Synthetic peptides, corresponding to these motifs in lactoferrin and lysozyme, exhibited AGE-binding activity. Since diabetes is associated with abnormally high levels of tissue and serum AGEs, the elevated AGEs may inhibit endogenous antibacterial proteins by binding to the conserved ABCD motif, thereby increasing susceptibility to bacterial infections in diabetic individuals. These results may provide a basis for the development of new approaches to prevent diabetic infections.
Picower Institute for Medical Research, Manhasset, New York 11030, USA.
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D000595:Amino Acid Sequence; D001424:Bacterial Infections / Q000188:drug therapy / Q000378:metabolism*; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008024:Ligands; D008969:Molecular Sequence Data
D008024:Ligands; D007781:Lactoferrin