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pH stability of HLA-DR4 complexes with antigenic peptides
M P Belmares1, J D Rabinowitz, W Liu
1Department of Chemistry, Stanford University, Stanford, California 94305, USA.
Biochemistry
|November 23, 2000
Summary
Major histocompatibility complex (MHC) peptide complexes show unusual pH-dependent dissociation. This occurs when acidic residues are buried in neutral pockets, impacting cellular immune responses and autoimmunity.
Area of Science:
- Immunology
- Biochemistry
- Structural Biology
Background:
- Major histocompatibility complex (MHC) class II peptide complexes are crucial for cellular immune responses.
- These complexes typically dissociate faster at acidic pH (intracellular) than neutral pH (cell surface).
Purpose of the Study:
- To investigate the pH-dependent dissociation kinetics of MHC class II peptide complexes.
- To understand how the location of aspartic and glutamic acid residues affects complex stability.
Main Methods:
- Analysis of dissociation kinetics of various MHC-peptide complexes across different pH levels.
- Kinetic data analysis using a protonation equilibrium model.
Main Results:
- Some MHC-peptide complexes exhibit inverse pH dependence, dissociating faster at neutral pH (7) than acidic pH (5.3).
- This unusual behavior is linked to buried carboxylate groups of peptide residues in neutral protein pockets.
- A protonation equilibrium model accurately describes the observed kinetics, with pKa values ranging from 7.7 to 8.3.
Conclusions:
- The microenvironment of peptide residues within MHC class II molecules significantly influences complex stability and pH dependence.
- Buried acidic residues in neutral pockets can lead to enhanced stability at neutral pH, a finding relevant to autoimmunity.
- This study provides insights into the chemical basis of autoimmune diseases mediated by specific MHC-peptide interactions.