Lecture Series: "Methyl-based NMR studies of dynamic protein complexes involved in immune recognition"

Methyl-based NMR studies of dynamic protein complexes involved in immune recognition

1,2Andrew C. McShan, 3Christine A. Devlin, 1,2Hau V. Truong,  3Erik Procko and 1,2Nikolaos G. Sgourakis

1Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia 

2Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, 3401 Civic Center Blvd, Philadelphia, PA, 19104, USA

3Department of Biochemistry and Cancer Center at Illinois, University of Illinois, Urbana, IL 61801, USA.

The class-I proteins of the major histocompatibility complex (MHC-I) capture and display antigenic peptides derived from the processing of intracellular targets to cytotoxic T-cells and natural killer cells for immune surveillance. Human MHC proteins, referred to as human leukocyte antigens (HLA), are highly polymorphic with over 10,000 distinct allotypes identified to date. Despite structural similarities, allelic sequence diversity has been shown to influence interactions with dedicated molecular chaperones, Tapasin and TAPBPR, along the MHC-I antigen processing and quality control pathway. Mounting biophysical and functional data highlight the role of protein dynamics in fine-tuning MHC-I/chaperone interactions for proper folding and peptide selector function. This seminar will present insights from NMR experiments designed to probe dynamic motions spanning a range of timescales and degrees of freedom, combined with deep mutational scanning for probing functionally important residues on both MHC-I and chaperone structures. Taken together, our results outline a paradigm where the intrinsic conformational plasticity of key MHC-I surfaces determine chaperone recognition, and peptide repertoire selection.

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