Biochemical and structural characterization of the human TL1A ectodomain.
TNF-like 1A (TL1A) is a newly described member of the TNF superfamily that is directly implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, atherosclerosis, and rheumatoid arthritis. We report the crystal structure of the human TL1A extracellular domain at a resolution of 2.5 A, which reveals a jelly-roll fold typical of the TNF superfamily. This structural information, in combination with complementary mutagenesis and biochemical characterization, provides insights into the binding interface and the specificity of the interactions between TL1A and the DcR3 and DR3 receptors. These studies suggest that the mode of interaction between TL1A and DcR3 differs from other characterized TNF ligand/receptor complexes. In addition, we have generated functional TL1A mutants with altered disulfide bonding capability that exhibit enhanced solution properties, which will facilitate the production of materials for future cell-based and whole animal studies. In summary, these studies provide insights into the structure and function of TL1A and provide the basis for the rational manipulation of its interactions with cognate receptors.
Zhan
Chenyang
C
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Yan
Qingrong
Q
Patskovsky
Yury
Y
Li
Zhenhong
Z
Toro
Rafael
R
Meyer
Amanda
A
Cheng
Huiyong
H
Brenowitz
Michael
M
Nathenson
Stanley G
SG
Almo
Steven C
SC
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D053323:Receptors, Tumor Necrosis Factor, Member 6b / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000737:chemistry* / Q000235:genetics
D004220:Disulfides; D053323:Receptors, Tumor Necrosis Factor, Member 6b; C505911:TNFRSF6B protein, human; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15