Tumor necrosis factor receptor superfamily

Area of Science:

• Structural Biology
• Immunology
• Biochemistry

Background:

• Tumor necrosis factor (TNF) is a key cytokine in immune and inflammatory responses.
• TNF signaling is mediated by TNF receptors (TNF-R1 and TNF-R2).
• Receptor activation involves ligand binding, aggregation, and endocytosis.

Purpose of the Study:

• To determine the structure of the soluble extracellular domain of TNF-R1 (sTNF-R1) at low pH.
• To understand the structural basis of TNF-R1 function during endocytosis and signaling.
• To identify conserved structural units within the TNF-R superfamily.

Main Methods:

• X-ray crystallography of sTNF-R1 at pH 3.7 (two forms) and pH 7.5.
• Analysis of protein structure, including disulfide connectivity and buried surface area.
• Identification and comparison of structural modules.

Main Results:

• The structure of sTNF-R1 was determined at 1.85 Å resolution at low pH.
• Unliganded sTNF-R1 exists as a dimer in all crystal forms.
• A novel low pH dimer buries significant surface area, distinct from the TNF-bound complex.
• Two conserved structural modules (Type A and Type B) were identified in sTNF-R1.

Conclusions:

• The low pH dimer likely plays a role in dissociating the TNF-receptor complex during endocytosis.
• Structural modules, rather than cysteine subdomains, represent conserved units in TNF-R1.
• This modular understanding facilitates modeling of the broader TNF-R superfamily.