title: Biochemical and Structural Characterization of the Interaction between the Siderocalin NGAL/LCN2 (Neutrophil Gelatinase-associated Lipocalin/Lipocalin 2) and the N-terminal Domain of Its Endocytic Receptor SLC22A17.
abstract: The neutrophil gelatinase-associated lipocalin (NGAL, also known as LCN2) and its cellular receptor (LCN2-R, SLC22A17) are involved in many physiological and pathological processes such as cell differentiation, apoptosis, and inflammation. These pleiotropic functions mainly rely on NGAL's siderophore-mediated iron transport properties. However, the molecular determinants underlying the interaction between NGAL and its cellular receptor remain largely unknown. Here, using solution-state biomolecular NMR in conjunction with other biophysical methods, we show that the N-terminal domain of LCN2-R is a soluble extracellular domain that is intrinsically disordered and interacts with NGAL preferentially in its apo state to form a fuzzy complex. The relatively weak affinity (≈10 μm) between human LCN2-R-NTD and apoNGAL suggests that the N terminus on its own cannot account for the internalization of NGAL by LCN2-R. However, human LCN2-R-NTD could be involved in the fine-tuning of the interaction between NGAL and its cellular receptor or in a biochemical mechanism allowing the receptor to discriminate between apo- and holo-NGAL.
authors.affiliation: From the Department of Computational and Structural Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Ana-Isabel
authors.initials: AI
authors.lastname: Cabedo Martinez
authors.affiliation: From the Department of Computational and Structural Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Weinhäupl
authors.affiliation: Chair of Physiology, Pathophysiology, and Toxicology and ZBAF, Faculty of Health, School of Medicine, Witten/Herdecke University, Stockumer Strasse 12, 58453 Witten, Germany.
authors.forename: Wing-Kee
authors.initials: WK
authors.lastname: Lee
authors.affiliation: Chair of Physiology, Pathophysiology, and Toxicology and ZBAF, Faculty of Health, School of Medicine, Witten/Herdecke University, Stockumer Strasse 12, 58453 Witten, Germany.
authors.forename: Natascha A
authors.initials: NA
authors.lastname: Wolff
authors.affiliation: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB, Innrain 80/82, 6020 Innsbruck, Austria, and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Storch
authors.affiliation: Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Żerko
authors.affiliation: From the Department of Computational and Structural Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Konrat
authors.affiliation: Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland.
authors.forename: Wiktor
authors.initials: W
authors.lastname: Koźmiński
authors.affiliation: Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, CCB, Innrain 80/82, 6020 Innsbruck, Austria, and.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Breuker
authors.affiliation: Chair of Physiology, Pathophysiology, and Toxicology and ZBAF, Faculty of Health, School of Medicine, Witten/Herdecke University, Stockumer Strasse 12, 58453 Witten, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Thévenod
authors.affiliation: From the Department of Computational and Structural Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria, nicolas.coudevylle@univie.ac.at.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Coudevylle
mesh_terms: D000209:Acute-Phase Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019906:Nuclear Magnetic Resonance, Biomolecular; D027701:Organic Cation Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D027701:Organic Cation Transport Proteins; D011518:Proto-Oncogene Proteins; C518841:SLC22A17 protein, human
keywords: cell surface protein; fuzzy complex; intrinsically disordered protein; lipocalin 2; membrane protein; neutrophil gelatinase-associated lipocalin receptor; protein complex; protein-protein interaction