title: Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration.
abstract: Siderocalin, a member of the lipocalin family of binding proteins, is found in neutrophil granules, uterine secretions, and at markedly elevated levels in serum and synovium during bacterial infection; it is also secreted from epithelial cells in response to inflammation or tumorigenesis. Identification of high-affinity ligands, bacterial catecholate-type siderophores (such as enterochelin), suggested a possible function for siderocalin: an antibacterial agent, complementing the general antimicrobial innate immune system iron-depletion strategy, sequestering iron as ferric siderophore complexes. Supporting this hypothesis, siderocalin is a potent bacteriostatic agent in vitro under iron-limiting conditions and, when knocked out, renders mice remarkably susceptible to bacterial infection. Here we show that siderocalin also binds soluble siderophores of mycobacteria, including M. tuberculosis: carboxymycobactins. Siderocalin employs a degenerate recognition mechanism to cross react with these dissimilar types of siderophores, broadening the potential utility of this innate immune defense.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Holmes
authors.forename: Wendy
authors.initials: W
authors.lastname: Paulsene
authors.forename: Xu
authors.initials: X
authors.lastname: Jide
authors.forename: Colin
authors.initials: C
authors.lastname: Ratledge
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
mesh_terms: D000209:Acute-Phase Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008024:Ligands; D000071068:Lipocalin-2; D054834:Lipocalins; D008958:Models, Molecular; D009164:Mycobacterium Infections / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D015513:Oncogene Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins; D017262:Siderophores / Q000378:metabolism*; D012995:Solubility; D013059:Spectrum Analysis, Raman; D055672:Static Electricity
chemical_list: D000209:Acute-Phase Proteins; D000900:Anti-Bacterial Agents; D007502:Iron Chelating Agents; C489506:LCN2 protein, human; D008024:Ligands; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D017262:Siderophores; D007501:Iron