|
Antigens encoded by the
major histocompatibility complex (MHC, HLA complex in human) play a central
role in the immune response. MHC class I molecules accommodate small peptide
fragments of 8 to 12 amino acids within a binding groove and present them to T
cell receptors on cytotoxic T cells. T cells constitute a necessary component
of normal adaptive immune responses, but can also be involved in autoimmunity.
A wealth of structural information on MHC:peptide complexes has become
available, but the static picture resulting from crystallographic studies has
not been able to fully explain several features of the interaction between
these molecules. We will employ heteronuclear NMR spectroscopy in conjunction
with extensive labeling to investigate the dynamics of the peptide and the MHC
class I binding groove at physiological temperature. By comparing peptides in
complex with HLA-B27 subtypes that differ only by a single amino acid exchange
from each other, but are differentially associated with an autoimmune disease,
we will correlate the dynamic and structural attributes with distinct
functional properties of these peptide-loaded molecules. |
