Dynamic Influence of the Two Membrane-Proximal Immunoglobulin-Like Domains upon the Peptide-Binding Platform Domain in Class I and Class II Major Histocompatibility Complexes: Normal Mode Analysis

Abstract

1193Major histocompatibility complexes (MHCs) are cell-surface glycoproteins that play an important role in immune response against infection. MHCs bind to a small peptide derived from either host or pathogen proteins, and present them to a T cell as a part of the immune system's mechanism for identifying and responding to foreign antigens. The engagement of an MHC molecule with a peptide by an antigen receptor on a cell causes the stimulation of the T cell and the activation of the immune response. The striking characteristic of MHCs is their ability to bind to various peptides in order to ensure an immune response against many possible pathogens.MHCs mainly fall into class I and class II. Class I MHC is composed of a heavy chain and a b 2 -immunoglobulin (b 2 m). The heavy chain is divided into three domains, a1, a2 and a3. The a1 and a2 domains are also functionally expressed as a peptide-binding platform domain, as the two domains are complicatedly intertwined. The platform domain forms an eight-stranded b-sheet and two a-helical regions, and a bound peptide is accommodated between the two a-helical regions on the b-sheet (Fig. 1A).1) The a3 and b 2 m domains are known as the membrane-proximal immunoglobulin-like domains because they are located between the platform domain and the cell surface.Conversely, class II MHC is composed of two asymmetric chains, the a-and b-chains, divided into the a1 and a2 domains, and the b1 and b2 domains, respectively. Thus the a1 and b1 domains come from different chains, but the two domains are also functionally expressed as a peptide-binding platform domain, because they are complicatedly intertwined. Surprisingly, the platform, b2 and a2 domains of class II MHC are very similar in structure to the platform, a3 and b 2 m domains of class I MHC, respectively (Figs. 1A, B).2,3) However, there is a difference in peptide-binding between both classes: Class I MHC binds to the peptide limited in length, usually 8-10 residues, 4-6) while class II MHC binds to the peptide without apparent restriction in length (ca. 8-23 amino acids in length). 7,8) Previous studies concerning MHCs were interested in the crystal structure of the platform domain required for peptidebinding and presenting to T cells. [1][2][3][4][5][6][7][8][9] Moreover, some experimental and theoretical studies of the peptide-free platform domain have received attention because its structure has not yet been crystallized in both classes. [10][11][12][13][14][15][16][17][18][19][20] On the other hand, the two membrane-proximal domains have attracted less interest than the platform domain. Some biochemical studies investigated the two membrane-proximal domains of class I MHC, suggesting the importance of b 2 m in peptide-binding. 21,22) However, there are no experimental or theoretical studies concerning the two membrane-proximal domains of class II MHC.In this study, we simulated the dynamics of a whole and partial model deficient in either of the two membrane-proximal domains for class I and class II using normal mod...

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Identification of new MUC1 epitopes using HLA-transgenic animals: implication for immunomonitoring

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Computational Analysis on the Binding of Epitope Peptide to Human Leukocyte Antigen Class I Molecule A*2402 Subtype

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