Cabedo Martinez Ana-Isabel, Weinhäupl Katharina, Lee Wing-Kee, Wolff Natascha A, Storch Barbara, Żerko Szymon, Konrat Robert, Koźmiński Wiktor, Breuker Kathrin, Thévenod Frank, Coudevylle Nicolas
From the Department of Computational and Structural Biology, Max F. Perutz Laboratories, University of Vienna, Campus Vienna Biocenter 5, 1030 Vienna, Austria.
Chair of Physiology, Pathophysiology, and Toxicology and ZBAF, Faculty of Health, School of Medicine, Witten/Herdecke University, Stockumer Strasse 12, 58453 Witten, Germany.
J Biol Chem. 2016 Feb 5;291(6):2917-30. doi: 10.1074/jbc.M115.685644. Epub 2015 Dec 3.
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.
中性粒细胞明胶酶相关脂质运载蛋白（NGAL，也称为LCN2）及其细胞受体（LCN2-R，SLC22A17）参与许多生理和病理过程，如细胞分化、凋亡和炎症。这些多效性功能主要依赖于NGAL的铁载体介导的铁转运特性。然而，NGAL与其细胞受体之间相互作用的分子决定因素在很大程度上仍然未知。在这里，我们结合溶液态生物分子核磁共振和其他生物物理方法表明，LCN2-R的N端结构域是一个可溶的细胞外结构域，其本质上是无序的，并且在其脱辅基状态下优先与NGAL相互作用形成模糊复合物。人LCN2-R-NTD与脱辅基NGAL之间相对较弱的亲和力（≈10μm）表明，其N端自身不能解释LCN2-R介导的NGAL内化。然而，人LCN2-R-NTD可能参与NGAL与其细胞受体之间相互作用的微调，或参与一种使受体能够区分脱辅基和全蛋白NGAL的生化机制。
