9.A.75. The MHC II Receptor (MHC2R) Family
This family consists of a complex of 3 proteins, DQ α-1, DQ β-1, which together comprise a heterodimer, and CD74, a homotrimer that forms a nanomeric complex with three DQ α/β dimers. CD74 plays a role in MHC class II antigen processing by stabilizing the peptide-free class II alpha/beta heterodimers in a complex soon after their synthesis, and directing transport of the complex from the endoplasmic reticulum to the endosomal/lysosomal system where the antigen processing and binding of antigenic peptides to MHC class II (DG α-1/DG β-1) takes place. CD74 also serves as cell surface receptor for the cytokine MIF. MHC II binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. The removal of the CD74-derived CLIP peptide is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class II molecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DM and MHC class II molecules is regulated by HLA-DO (Jiang et al. 2019; Santambrogio et al. 2019; Jurewicz and Stern 2019; Dijkstra and Yamaguchi 2019).
As noted above, an alpha and a beta subunit, also referred as MHC class II molecule, forms a heterononamer; 3 MHC class II molecules bind to a CD74 homotrimer (also known as invariant chain or HLA class II histocompatibility antigen gamma chain). In the endosomal/lysosomal system; CD74 undergoes sequential degradation by various proteases, leaving a small fragment termed CLIP (see above) on each MHC class II molecule. An MHC class II molecule interacts with HLA_DM, and HLA_DO in the B-cells, in order to release CLIP and facilitate the binding of antigenic peptides (Lee et al. 2001; Siebold et al. 2004; Kim et al. 2004; Henderson et al. 2007).
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The MHCII complex of three proteins, DQ alpha-1, DQ beta-1 (which form a heterodimer) and a CD75 homotrimer that together form a nanomer with 3 copies of the MHCII dimer. It transports antigenic peptides to the cell surface (Wosen et al. 2018). The structure, topology, and dynamics of membrane-inserted polypeptides and lipids have been examined by solid-state NMR spectroscopy, specifically with respect to the transmembrane domains of the DQ Beta-1 subunit of the MHC II receptor and the COP I protein, p24 (Salnikov et al. 2019).
MHC II complex of Homo sapiens
HLA class I histocompatibility antigen, HLA-A (HLAA), of 365 aas and 1 C-terminal TMS (Saunders and van Endert 2011). It acts with beta-2 (β-2) microglobulin B2M (P61769). There are many HLA antigens (HLAA, B, C, E, F and G, all homologous to each other and of 338 to 366 aas in length with a C-terminal TMS. Tapasin (TAPA, TABBP, NGS17 of 448 aas) is a necessary accessory protein for proper presentation of peptide antigens (Sadegh-Nasseri et al. 2008). A charged amino acyl residue in the transmembrane/cytoplasmic region of tapasin influences MHC class I assembly and maturation (Petersen et al. 2005). The human specific poxvirus molluscum contagiosum virus (MCV) has developed robust immune evasion strategies (Harvey et al. 2019). MCV-encoded MC80 can disrupt MHC-I antigen presentation in human and mouse cells. MC80 shares moderate sequence-similarity with MHC-I, and it associates with components of the peptide-loading complex. Expression of MC80 results in ER-retention of host MHC-I and thereby reduced cell surface presentation. MC80 accomplishes this by engaging tapasin via its luminal domain, targeting it for ubiquitination and ER-associated degradation in a process dependent on the MC80 transmembrane region and cytoplasmic tail. Tapasin degradation is accompanied by a loss of TAP, which limits MHC-I access to cytosolic peptides (Harvey et al. 2019).
HLA-A of Homo sapiens
Additional subunits of human HLA complexes including HLA-A (HLAA, 365 aas, P04439), HLA-B (HLAB, 203 aas, P01889), HLA-C (HLAC, 366 aas, P10321), and HLA_E (HLAE, 358 aas, P13747), all with two TMSs, N- and C-terminal.
HLA complex subunits with names similar but sequences dissimilar to/from those listed under TC#s 9.A.75.1.1 and 9.A.75.1.2 of Homo sapiens
The neonatal Fc receptor (FcRn), subunit p51 of 365 aas and one C-terminal TMS possibly with one N-terminal TMS as well. Early floral colonization affects intestinal immunoglobulin G uptake in piglets, which may be mediated by the NF-kappaB-FcRn pathway, with FcRn as the actual transmembrane carrier (Peng et al. 2023).
FcRn of Homo sapiens