Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex.
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.
Bao
Guanhu
G
College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Clifton
Matthew
M
Hoette
Trisha M
TM
Mori
Kiyoshi
K
Deng
Shi-Xian
SX
Qiu
Andong
A
Viltard
Melanie
M
Williams
David
D
Paragas
Neal
N
Leete
Thomas
T
Kulkarni
Ritwij
R
Li
Xiangpo
X
Lee
Belinda
B
Kalandadze
Avtandil
A
Ratner
Adam J
AJ
Pizarro
Juan Carlos
JC
Schmidt-Ott
Kai M
KM
Landry
Donald W
DW
Raymond
Kenneth N
KN
Strong
Roland K
RK
Barasch
Jonathan
J
D000209:Acute-Phase Proteins / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002396:Catechols / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D019295:Computational Biology; D018360:Crystallography, X-Ray; D011992:Endosomes / Q000378:metabolism; D005456:Fluorescent Dyes; D006801:Humans; D007501:Iron / Q000097:blood* / Q000737:chemistry; D007502:Iron Chelating Agents / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008024:Ligands; D000071068:Lipocalin-2; D054834:Lipocalins / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D015513:Oncogene Proteins / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D017262:Siderophores / Q000378:metabolism
D000209:Acute-Phase Proteins; D002396:Catechols; D005456:Fluorescent Dyes; D007502:Iron Chelating Agents; D008024:Ligands; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011994:Recombinant Proteins; D017262:Siderophores; C071332:Lcn2 protein, mouse; D007501:Iron