Parsing the functional specificity of Siderocalin/Lipocalin 2/NGAL for siderophores and related small-molecule ligands
| Autor: | Trisha M. Hoette, Rebecca J. Abergel, Kenneth N. Raymond, Matthew C. Clifton, Peter B. Rupert, Roland K. Strong |
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| Rok vydání: | 2019 |
| Předmět: |
Siderophore
HOPO hydroxypyridinone dihydroxybenzoic acid substrate-binding protein PBP bacterial periplasmic binding protein CMB Lipocalin AEB PBP DHBA dihydroxybenzoic acid Structural Biology BOCT brain-type organic cation receptor aerobactin Bacterial substrate binding proteins NGAL Neutrophil Gelatinase Associated Lipocalin PVD pyoverdine NGAL SBP bacterial membrane-associated substrate-binding protein lcsh:QH301-705.5 Ferric enterobactin/enterochelin bacterial membrane-associated 0303 health sciences CAM pyoverdine Chemistry 030302 biochemistry & molecular biology PCH c-di-GMP cyclic diguanylate monophosphate Small molecule FQ fluorescence quenching Transport protein schizokinen Biochemistry HOPO Infection ABC DHBA PDB Research Collaboratory for Structural Biology Protein Databank NE AU crystallographic asymmetric unit ENT fluorescence quenching Siderocalin ABC ATP‐binding cassette brain-type organic cation receptor DNA-binding protein Article norepinephrine CMB carboxymycobactin FQ 03 medical and health sciences carboxymycobactin CAM catechol c-di-GMP cyclic diguanylate monophosphate SBP PCH pyochelin hydroxypyridinone AEB aerobactin ComputingMethodologies_COMPUTERGRAPHICS X-ray crystallography 030304 developmental biology crystallographic asymmetric unit Innate immune system Ligand Inflammatory and immune system enterobactin or enterochelin Antimicrobial responses catechol SCH bacterial periplasmic binding protein PDB Research Collaboratory for Structural Biology Protein Databank pyochelin PVD Scn ENT enterobactin or enterochelin lcsh:Biology (General) BOCT Neutrophil Gelatinase Associated Lipocalin AU ATP‐binding cassette SCH schizokinen Scn Siderocalin NE norepinephrine |
| Zdroj: | Journal of Structural Biology: X, Vol 2, Iss, Pp-(2019) Journal of Structural Biology: X |
| ISSN: | 2590-1524 |
| DOI: | 10.1016/j.yjsbx.2019.100008 |
| Popis: | Graphical abstract Highlights • Ligand recognition by antibacterial Siderocalin controls the competition for iron during infection. • We determined nine crystal structures of Siderocalin mutants with ligands. • We determined three candidate ligands did not bind. • We determined the crystal structure of SBP YfiY. • Multiplexed specificity of Siderocalin was determined. Siderocalin/Lipocalin 2/Neutrophil Gelatinase Associated Lipocalin/24p3 is an innate immune system protein with bacteriostatic activity, acting by tightly binding and sequestering diverse catecholate and mixed-type ferric siderophores from enteric bacteria and mycobacteria. Bacterial virulence achieved through siderophore modifications, or utilization of alternate siderophores, can be explained by evasion of Siderocalin binding. Siderocalin has also been implicated in a wide variety of disease processes, though often in seemingly contradictory ways, and has been proposed to bind to a broader array of ligands beyond siderophores. Using structural, directed mutational, and binding studies, we have sought to rigorously test, and fully elucidate, the Siderocalin recognition mechanism. Several proposed ligands fail to meet rigorous binding criteria, including the bacterial siderophore pyochelin, the iron-chelating catecholamine hormone norepinephrine, and the bacterial second messenger cyclic diguanylate monophosphate. While possessing a remarkably rigid structure, in principle simplifying analyses of ligand recognition, understanding Scn recognition is complicated by the observed conformational and stoichiometric plasticity, and instability, of its bona fide siderophore ligands. Since the role of Siderocalin at the early host/pathogen interface is to compete for bacterial ferric siderophores, we also analyzed how bacterial siderophore binding proteins and enzymes alternately recognize siderophores that efficiently bind to, or evade, Siderocalin sequestration – including determining the crystal structure of Bacillus cereus YfiY bound to schizokinen. These studies combine to refine the potential physiological functions of Siderocalin by defining its multiplexed recognition mechanism. |
| Databáze: | OpenAIRE |
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