Iron traffics in circulation bound to a siderocalin (Ngal)–catechol complex

• Published in: Nature Chemical Biology Vol. 6; no. 8; pp. 602 - 609
• Main Authors: Strong, Roland K, Barasch, Jonathan, Bao, Guanhu, Clifton, Matthew, Hoette, Trisha M, Mori, Kiyoshi, Deng, Shi-Xian, Qiu, Andong, Viltard, Melanie, Williams, David, Paragas, Neal, Leete, Thomas, Kulkarni, Ritwij, Li, Xiangpo, Lee, Belinda, Kalandadze, Avtandil, Ratner, Adam J, Pizarro, Juan Carlos, Schmidt-Ott, Kai M, Landry, Donald W, Raymond, Kenneth N
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2010; Nature Publishing Group
• Subjects: 631/45/49/1140; 631/535; 631/92/321/1155; 631/92/609; Acute-Phase Proteins - chemistry; Acute-Phase Proteins - metabolism; Animals; Bacteria; Binding sites; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Catechols - blood; Catechols - chemistry; Catechols - metabolism; Cell Biology; Cell Line; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Chromatography, High Pressure Liquid; Computational Biology; Crystallography; Crystallography, X-Ray; Endosomes - metabolism; Fluorescence; Fluorescent Dyes; Humans; Iron; Iron - blood; Iron - chemistry; Iron Chelating Agents - metabolism; Kidney - metabolism; Ligands; Lipocalin-2; Lipocalins - blood; Lipocalins - chemistry; Lipocalins - metabolism; Mammals; Mice; Oncogene Proteins - blood; Oncogene Proteins - chemistry; Oncogene Proteins - metabolism; Protein Binding; Proteins; Recombinant Proteins - chemistry; Siderophores - metabolism
• ISSN: 1552-4450; 1548-7105; 1552-4469
• DOI: 10.1038/nchembio.402

The lipocalin protein Scn-Ngal is known to bind iron-chelating siderophores, leading to inhibition of bacterial growth. New results reveal that Scn-Ngal, in the absence of bacterial infection, can form a complex with catechol that binds and transports iron in vivo . The lipocalins are secreted proteins that bind small organic molecules. Scn-Ngal (also known as neutrophil gelatinase associated lipocalin, siderocalin, lipocalin 2) sequesters bacterial iron chelators, called siderophores, and consequently blocks bacterial growth. However, Scn-Ngal is also prominently expressed in aseptic diseases, implying that it binds additional ligands and serves additional functions. Using chemical screens, crystallography and fluorescence methods, we report that Scn-Ngal binds iron together with a small metabolic product called catechol. The formation of the complex blocked the reactivity of iron and permitted its transport once introduced into circulation in vivo . Scn-Ngal then recycled its iron in endosomes by a pH-sensitive mechanism. As catechols derive from bacterial and mammalian metabolism of dietary compounds, the Scn-Ngal–catechol–Fe (III) complex represents an unforeseen microbial-host interaction, which mimics Scn-Ngal–siderophore interactions but instead traffics iron in aseptic tissues. These results identify an endogenous siderophore, which may link the disparate roles of Scn-Ngal in different diseases.