Structure of the F-spondin domain of mindin, an integrin ligand and pattern recognition molecule.
Mindin (spondin-2) is an extracellular matrix protein of unknown structure that is required for efficient T-cell priming by dendritic cells. Additionally, mindin functions as a pattern recognition molecule for initiating innate immune responses. These dual functions are mediated by interactions with integrins and microbial pathogens, respectively. Mindin comprises an N-terminal F-spondin (FS) domain and C-terminal thrombospondin type 1 repeat (TSR). We determined the structure of the FS domain at 1.8-A resolution. The structure revealed an eight-stranded antiparallel beta-sandwich motif resembling that of membrane-targeting C2 domains, including a bound calcium ion. We demonstrated that the FS domain mediates integrin binding and identified the binding site by mutagenesis. The mindin FS domain therefore represents a new integrin ligand. We further showed that mindin recognizes lipopolysaccharide (LPS) through its TSR domain, and obtained evidence that C-mannosylation of the TSR influences LPS binding. Through these dual interactions, the FS and TSR domains of mindin promote activation of both adaptive and innate immune responses.
Li
Yili
Y
WM Keck Laboratory for Structural Biology, Center for Advanced Research in Biotechnology, University of Maryland Biotechnology Institute, Rockville, MD 20850, USA.
Cao
Chunzhang
C
Jia
Wei
W
Yu
Lily
L
Mo
Min
M
Wang
Qian
Q
Huang
Yuping
Y
Lim
Jae-Min
JM
Ishihara
Mayumi
M
Wells
Lance
L
Azadi
Parastoo
P
Robinson
Howard
H
He
You-Wen
YW
Zhang
Li
L
Mariuzza
Roy A
RA
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D018360:Crystallography, X-Ray; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051192:Receptors, Pattern Recognition / Q000737:chemistry* / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid; D055672:Static Electricity
D016326:Extracellular Matrix Proteins; D016023:Integrins; D008070:Lipopolysaccharides; D051192:Receptors, Pattern Recognition; C121491:mindin; D008358:Mannose; D002118:Calcium