Biochemical and Structural Characterization of the Human TL1A Ectodomain

Journal Article · Thu Jan 01 04:00:00 EST 2009 · Biochemistry

DOI:https://doi.org/10.1021/bi900031w· OSTI ID:980037

Zhan, C; Yan, Q; Patskovsky, Y; Li, Z; Toro, R; Meyer, A; Cheng, H; Brenowitz, M; Nathenson, S; Almo, S

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 {angstrom}, 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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 980037
• Report Number(s): BNL--92955-2010-JA
• Journal Information: Biochemistry, Journal Name: Biochemistry Journal Issue: 32 Vol. 48
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
ANIMALS
ARTERIOSCLEROSIS
BONDING
COMPLEXES
CRYSTAL STRUCTURE
DISEASES
DISULFIDES
FUNCTIONALS
FUNCTIONS
HUMAN POPULATIONS
INFORMATION
INTERACTIONS
INTERFACES
MATERIALS
MUTAGENESIS
MUTANTS
PATHOGENESIS
PRODUCTION
RECEPTORS
RESOLUTION
RHEUMATIC DISEASES
SOLUTIONS
SPECIFICITY
national synchrotron light source