The broad, long term goal ofthe proposed research is to understand the structure and function of MHC proteins and cellular factors that interact with therin. There are five specific ainns.
The first aim i s structural and mechanistic characterization of aminopeptidases involved in antigen processing. Recently we determined the X-ray crystal structure of ERAP1, an enzyme responsible for the final trimming of some peptide antigens so that they can be accommodated into the class I MHC binding site. In the proposed research we will extend structural studies to other aminopeptidases that have been implicated in antigen processing pathways, and we will evaluate a mechanistic model that we proposed to explain ERAPI's unusual length-dependent proteolytic activity.
The second aim i s to evaluate a mechanism proposed for HLA-DM action in facilitating peptide exchange from class II MHC proteins. Recently we determined the structure of HLA-DM, a catalytic peptide exchange factor, bound to HLA-DO, an inhibitor of peptide exchange. Kinetic and mutagenesis studies suggested that HLA-DO mimics the structure of an intermediate in the peptide exchange pathway. In the proposed research we will test a model for HLA-DM action, in which HLA-DM interaction with MHC induces concerted changes in the MHC 3-10 helix and adjacent extended strand region that lead to facilitated peptide exchange.
The third aim i s to determine the structural basis for MHC allele-specific interaction with DM and its potential as a mechanism to explain association of particular MHC alleles with autoimmunity. The class II MHC 3-10 helix.and adjacent extended strand region exhibit allele-dependent structural variation. We will test the hypothesis that this variation is related to HLADM susceptibility.
The fourth aim i s to understand how TCR chain pairing creates specificity for MHC-peptide complexes. How TCR are constructed to recognize a limited set of ligands is not clear. We will characterize interactions between TCR alpha subunit residues and beta subunit CDR loops, and vice versa, to determine how these shape MHC-TCR interaction. The fifth aim is to characterize the structural basis for T cell crossreactivity of epitopes from vaccina virus and lymphocytic choriomeningitis virus.

Public Health Relevance

In the proposed research the molecular structure and mechanism of MHC proteins and interacting partners will be elucidated. These proteins play key roles in antigen processing, which allows the immune system to survey the body for pathogens and tumors. Better understanding of MHC-peptide interactions and antigen processing pathways are necessary to improve our ability to predict the immune response to pathogenic oraanisms and autoimmune antigens, and to develop and improve vaccines and immunomodulatory agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37AI038996-16
Application #
8391771
Study Section
Special Emphasis Panel (NSS)
Program Officer
Gondre-Lewis, Timothy A
Project Start
1996-02-01
Project End
2018-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2013
Total Cost
$390,981
Indirect Cost
$155,981
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Yin, Liusong; Stern, Lawrence J (2014) A novel method to measure HLA-DM-susceptibility of peptides bound to MHC class II molecules based on peptide binding competition assay and differential IC(50) determination. J Immunol Methods 406:21-33
Parra-López, Carlos A; Bernal-Estévez, David; Yin, Liusong et al. (2014) An unstable Th epitope of P. falciparum fosters central memory T cells and anti-CS antibody responses. PLoS One 9:e100639
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Painter, Corrie A; Negroni, Maria P; Kellersberger, Katherine A et al. (2011) Conformational lability in the class II MHC 310 helix and adjacent extended strand dictate HLA-DM susceptibility and peptide exchange. Proc Natl Acad Sci U S A 108:19329-34