# Molecular mechanism of antigen editing by Class-I MHC Chaperones

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $557,933

## Abstract

Summary
 I propose to develop and apply innovative structural biology and protein engineering tools to
investigate the molecular mechanism of antigen editing and display on major histocompatibility
complex (MHC or HLA in humans) molecules. The MHC encodes the most polymorphic proteins in
the human genome, and is associated with more diseases than any other region. Unravelling the
function of these proteins will help us understand autoimmune diseases, such as diabetes, multiple
sclerosis and arthritis, and immune responses to viral pathogens and developing tumors. In particular,
Class-I proteins encoded by the MHC (MHC-I) play a pivotal role in alerting the rest of the immune
system to peptide antigens, derived from self-proteins, intracellular pathogens or tumors, by
interacting with clonotypic T cell receptors (TCRs) expressed by cytotoxic CD8+ T cells. Key to the
assembly of properly conformed MHC-I with bound peptide antigen are molecular chaperones that
actively select high-affinity peptides for the displayed repertoire. Besides the basic science merit,
characterizing this mechanism in atomic detail has important clinical implications, as suggested by
immunodeficiencies resulting from dysregulation of the peptide-loading process, the downregulation
of chaperone functions in tumors, and the direct targeting of chaperones by viral immune evasion
strategies.
 Despite a large number of functional and structural studies, the use of conventional methods
has proven ineffective for elucidating the 3D structure of the MHC-I/chaperone complex together with
bound peptides. This is due to the highly dynamic nature of peptide interactions within the
chaperoned MHC-I groove. As a result, the crucial conformational changes needed for antigen editing
remain incompletely characterized. To remove these bottlenecks, I have developed a new
methodology that combines complementary datasets from NMR and cryoEM with the computational
modeling program, Rosetta, to obtain high-resolution structures of such challenging complexes.
 Here, I propose to apply this powerful integrative modeling approach to characterize
chaperone complexes with human HLA molecules, and to elucidate dynamic transitions between
peptide conformations which govern antigen editing. Our structural results will be further explored
using protein directed evolution, and explicitly addressed in a cellular context using functional
experiments, followed by a detailed proteomic analysis. As a long-term goal, I plan to use a structure-
guided approach to engineer novel chaperone functions with custom specificities, to be used in
emerging immunotherapy applications against graft rejection, autoimmune diseases, pathogen
infection and cancer.

## Key facts

- **NIH application ID:** 10201060
- **Project number:** 7R01AI143997-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Nikolaos Sgourakis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $557,933
- **Award type:** 7
- **Project period:** 2019-01-21 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201060

## Citation

> US National Institutes of Health, RePORTER application 10201060, Molecular mechanism of antigen editing by Class-I MHC Chaperones (7R01AI143997-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10201060. Licensed CC0.

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