What is the difference between mhc 1 and 2

When it comes to genes, each gene in our body has a large number of alleles. Alleles are nothing but the alternate form of genes that are capable of producing alternate forms of proteins. The MHC also contains a number of other genes that code for other proteins. During the early s, when the skin graft experiments used to be carried out in mice, there were graft rejections. And these graft rejections were concluded saying that it was immune reactions by the host organism against the foreign matter or tissue.

The MHC molecules on the cells of the graft tissue were recognized by the host as the foreign antigen. Therefore, for successful organ transplantation, it was necessary that the tissue type of the donor and the receiver should be similar to a large extent. These are present in all the cells which are nucleated including platelets and except red blood cells. Macrophages are the most professional phagocytes that engulf bacteria and virus-like foreign particles.

Dendritic cells are also a type of phagocytes that present antigens to T cells. B cells produce antibodies during humoral immunity. MHC class 2 molecules present exogenous antigens. The exogenous antigens are originated extracellularly from bacteria-like foreign particles. The phagocyted pathogens are degraded inside the antigen presenting cells and peptide fragments are presented on the cell membrane with the help of MHC class 2 molecules.

These antigens are recognized by helper T cells, activating them. The activated helper T cells release lymphokines, attracting other cells that destroy the antigenic material. MHC Class 1: MHC class 1 are a class of major histocompatibility complex molecules found on the surface of all nucleated cells in mammals. MHC Class 2: MHC class 2 are a class of major histocompatibility complex molecules mainly found on antigen presenting cells such as macrophages, dendritic cells, and B cells.

MHC Class 2: MHC class 2 molecules present exogenous antigens originated extracellularly from foreign bodies such as pathogens. Additionally, two peptide editors—tapasin for class I and HLA-DM for class II—contribute to the shaping of the presented peptidome by favoring the binding of high-affinity antigens.

Although there is a vast amount of biochemical and structural information, the mechanism of the catalyzed peptide exchange for MHC class I and class II proteins still remains controversial, and it is not well understood why certain MHC allelic variants are more susceptible to peptide editing than others.

Recent studies predict a high impact of protein intermediate states on MHC allele-specific peptide presentation, which implies a profound influence of MHC dynamics on the phenomenon of immunodominance and the development of autoimmune diseases. Here, we review the recent literature that describe MHC class I and II dynamics from a theoretical and experimental point of view and we highlight the similarities between MHC class I and class II dynamics despite the distinct functions they fulfill in adaptive immunity.

Major histocompatibility complex MHC class I and class II proteins play a pivotal role in the adaptive branch of the immune system. Both classes of proteins share the task of presenting peptides on the cell surface for recognition by T cells. In all cases, it is a clonotypic T cell receptor that interacts with a given pMHC complex, potentially leading to sustained cell:cell contact formation and T cell activation.

Major histocompatibility complex class I and class II share an overall similar fold. Two membrane-proximal immunoglobulin Ig domains support the peptide-binding unit. Figure 1. The peptide is shown in yellow with its N and C-terminus marked and relevant pockets are labeled green C Simplified illustration of MHC class I left and II right processing and peptide-editing pathways.

The type of interactions of individual peptide side-chains with the MHC depend on the geometry, charge distribution, and hydrophobicity of the binding groove. Predicting the affinity of these distinct MHC—antigen interactions for individual allotypes has been a long-standing goal in the community.

While good progress has been made in developing and optimizing bioinformatic algorithms to estimate peptide binding to MHC proteins, these in silico predictions, however, still yield false positives 5 , 6 , and often fail in predicting immunodominance. We argue that understanding the relevance of transient or energetically excited protein conformations that are visited during the equilibrium fluctuations of the molecular structure is important for making good predictions.

In MHC class I, the binding groove is closed at both ends by conserved tyrosine residues leading to a size restriction of the bound peptides to usually 8—10 residues with its C-terminal end docking into the F-pocket 7 — 9.

In contrast, MHC class II proteins usually accommodate peptides of 13—25 residues in length in their open binding groove, with the peptide N-terminus usually extruding from the P1 pocket It has been reported that the interactions at the F pocket region in MHC class I and the P1 region including the P2 site in MHC class II appear to have a dominant effect on the presentation of stable pMHC complexes and on the immunodominance of certain peptidic epitopes 11 — A good match of the peptide and the MHC binding groove is an important, but certainly not the sole determinant of its presentation.

In fact, the formation of a pMHC complex depends on its peptide-loading pathway, in which the selection of peptides is influenced by several factors, such as antigen availability, protease activity, or the availability of chaperones. These molecules edit the presented peptide repertoire and bias the exchange reaction toward the presentation of thermodynamically stable complexes. Tapasin and HLA-DM thus act similar to typical enzymes by reducing the energy barrier for peptide exchange.

However, in the case of HLA-DM and tapasin, no covalent bonds are formed or cleaved during the exchange reaction. The partially folded heterodimer is then incorporated into the peptide-loading complex PLC for peptide binding and exchange.

In the PLC, tapasin is a protein that catalyzes, together with other chaperones, the loading of high-affinity peptides derived from proteolysis of endogenously expressed proteins Figure 1 C, left panel 17 , This placeholder peptide is then normally exchanged against higher affinity peptides, which are derived from proteolytically degraded proteins available in endocytic compartments Figure 1 C, right panel.

HLA-DM accelerates peptide exchange, with different allelic variants being more or less susceptible to catalysis. Despite the structural differences between tapasin and HLA-DM as well as their presumably opposite sites of interaction with regard to the orientation of the binding groove, a similar mode of action has been suggested, hinting at a possible convergent evolution of the two exchange catalysts Figure 1 B A common feature seems to be that both catalysts target regions in the vicinity of those pockets in the peptide-binding groove that are of great relevance for the stability of the respective pMHC complex 11 , 13 , 15 , 31 , While the general hallmarks of antigen processing and editing have been established, the discussion is now moving toward the dynamics of the system, both at the cellular and molecular level.

The mechanistic questions relate to a description of how exactly peptides are selected for presentation and how tapasin and HLA-DM catalyze this reaction in an allele-specific manner. In contrast, increasing experimental and computational evidence of wild type WT and mutant MHC complexes over the past years incontestably revealed that changes in conformational dynamics in MHC proteins have to accompany peptide loading and exchange 22 , 40 — To highlight possible dynamic regions within ground-state crystal structures of human MHC class I and class II proteins bound to a peptide, we performed a global B-factor analysis of all available X-ray crystal structures of human MHC complexes in the absence of any other binding partner.

In each structure, we normalized the B-factor values of each alpha carbon CA atom to the global mean. Our analysis is corroborated by a previous comparison of 91 different pMHC class II crystal structures Figure 2. It is known that, to some extent, structural variations can be introduced by variable peptide-binding modes. In this context, peptides longer than 8—10 residues have been reported to bind to the MHC class I binding groove 48 — This is usually achieved by a kink in the backbone in the middle part of the peptide.

Recently, two crystal structures of HLA-A2 bound tomer peptides have been solved The two peptides follow a binding mode similar to that of the canonical peptides with two anchor residues in the B and F pockets. Furthermore, although the binding of the N- and C-termini at both ends of the binding groove is conserved in almost all the MHC class I complexes, some exceptions have been reported. Another example is seen in the HLA-B35 protein, the short N-terminus of the 8-mer peptide does not reach the A pocket.

Instead, the hydrogen bonds between the amino group of P1 residue and residue 45 of MHC class I are mediated by a water molecule Since, in the case of MHC class II proteins, the peptide ligand within the binding groove usually adopts a pseudosymmetrical PPII helix-like conformation, bidirectional binding is theoretically possible. Biological and biochemical evidence for the existence of other pMHC class II isomers have been described in the context of autoimmunity Since MHC class II proteins have open binding grooves, peptides can protrude outwards and even bind in different registers.

In this regard, an insulin B chain-derived peptide InsB 9—23 was suggested to induce type 1 diabetes T1D in a thermodynamically less favored, low-affinity binding register 60 , Apart from variable peptide binding, catalyst binding can induce more significant conformational variation, as seen in DM-bound DR.

Compared to other parts of the pMHC class II structure, it was shown that this site indeed represents a conformationally labile region 35 , Figure 3. Conformational rearrangements upon DM binding and structural variations in type 1 diabetes-susceptible DQ complexes.

B DM-induced rearrangements in the P1-pocket and the surrounding helical segments. The decrease in DM-susceptibility of these two proteins was explained by a stabilization of the 3 10 helical region 63 Figure 3 C. However, the exact relationship between structural variations in the 3 10 helix and DM-susceptibility are not clear, as highly DM-susceptible DR complexes can display a different conformational mode, compared to DM-susceptible DQ alleles Figure 3 D.

The observed changes lead to the question as to how much structural plasticity in these regions preexists in the peptide-loaded form and provide a prerequisite for catalyzed as well as for spontaneous peptide exchange. For example, do pMHC complexes sample conformations observed in simulations of empty proteins or in complex with the catalyst? How would allelic variation affect the distribution of MHC proteins within the conformational space and thereby influence the presented peptide repertoire?

Could variation in protein plasticity also account for the association of specific MHC alleles with immune diseases? Since the polymorphic peptide-binding groove of MHC proteins defines its affinity for a certain peptide, substitutions of even a single amino acid may lead to significantly different affinities for individual peptides. In general, the critical factors defining whether a peptide is presented or not are determined at the different levels of antigen processing and presentation such as uptake route, amount, and folding state of the antigenic protein, amenability to proteolytic degradation, and catalysis of the complex, etc.

However, at the molecular level, it has been shown that certain polymorphisms shape individual pockets in the peptide-binding groove to optimally present an autoimmunogenic self-peptide 65 — In other cases, the functional impact of disease-associated polymorphisms remained enigmatic and suggests that dynamics might account for the observed differences. While simulations and experimental studies vary in the features ascribed to peptide-free MHC proteins, they certainly agree in attributing a substantial degree of dynamics to the peptide-binding groove.

Thus, binding of peptides to MHC proteins is of utmost importance for the stabilization of the known MHC fold 40 , The lack of a crystal or an NMR structure of peptide-free MHC protein hinders an accurate description of the structural changes upon peptide binding and this is probably due to the ensemble character of the peptide-free conformers.

This ensemble character, however, has been probed by computational techniques, as discussed in the following paragraphs. Most of the conformational dynamics information on the peptide-free class I have been revealed by molecular dynamics MD simulations. In such simulations, peptide-free class I protein is modeled from the crystal structure by deleting the atoms of the bound peptide.

Longer simulations of chicken and human class I allotypes showed increased global motion in the peptide-free form when compared to the peptide-bound proteins 72 , By combining molecular docking and MD simulations, a conformational transition of the 3 10 helical segment of H-2L d between the peptide-bound and peptide-free class I was observed.

Thus, a conformational reorganization close to the A and B pockets upon peptide binding was proposed Saini et al. The results pointed to a folding intermediate of peptide-free class I proteins that are more structured than a molten globule This was in line with a previous study arguing for a native-like conformation of in vitro refolded empty murine class I proteins This is consistent with previous reports indicating that especially the binding groove is undergoing conformational exchange in the absence of the bound peptide 40 , A work that focused on complexes with a partly filled MHC class I binding groove pointed to a requirement of the stabilization of the F pocket region.

To stabilize peptide-free class I in a folded form independently from the peptide, the Springer group created a novel variant by introducing a disulfide bond to restrain the high flexibility of the F pocket region.

Physiologically, the question if peptide-free MHC class II proteins play a role in adaptive immunity is posed by studies indicating that unloaded MHC class II proteins are abundantly present on the surface of immature DCs.

There, they are able to bind ligands from the extracellular milieu and activate T cells 81 , Two isomers of peptide-unloaded MHC proteins seem to exist, each displaying different kinetic properties While the peptide-receptive empty isomer of DR1 binds peptide rapidly, the conversion to the non-receptive isomer within less than 5 min dramatically reduces the peptide-binding capacity of human DR 41 , 84 , Studies using circular dichroism and size exclusion chromatography predicted a conformational change of peptide-free MHC class II upon peptide binding, and an increase in the overall stability 44 , 68 , Carven and Stern studied ligand-induced conformational changes by selective chemical side-chain modification of peptide-free DR1 followed by mass spectroscopy analysis The results of this study were inconsistent with a partly unfolded state of DR1 in the absence of ligand, but rather indicated a more localized conformational change induced upon peptide binding.

Last updated on June 11th, Immunity is defined as the resistance offered by the host against microorganisms or any other foreign substance s. Immunity can be broadly classified into two types: Innate Immunity-present right from […].

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