---
title: "Major Histocompatibility Complex I - Definition, Structure, Mechanism, Functions"
description: "Get Free Biology Notes"
url: https://biologynotesonline.com/major-histocompatibility-complex-i/
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# Major Histocompatibility Complex I – Definition, Structure, Mechanism, Functions

Major Histocompatibility Complex class I (MHC I) is a cell surface glycoprotein which is found on almost all nucleated cells and platelets. In human it is known as Human Leukocyte Antigen (HLA). The main classical forms are HLA-A, HLA-B and HLA-C. MHC I is heterodimer in structure. It is made up of one heavy alpha ... [Read more](https://biologynotesonline.com/major-histocompatibility-complex-i/)

**Major Histocompatibility Complex class I (MHC I)** is a cell surface glycoprotein which is found on almost all nucleated cells and platelets. In human it is known as **Human Leukocyte Antigen (HLA)**. The main classical forms are **HLA-A**, **HLA-B** and **HLA-C**.

**MHC I** is heterodimer in structure. It is made up of one heavy **alpha chain** and one small **beta-2-microglobulin** chain. These two chain form the groove like area for peptide binding. The groove is closed at both end and so it binds only short peptide, generally 8-11 amino acids.

The main work of **MHC I** is presentation of endogenous antigen. Endogenous antigen means the antigen which are formed inside the cell. These may be normal self protein or abnormal protein. Viral protein, intracellular bacterial protein and tumour protein also comes under this.

In the cytoplasm, protein are degraded by **proteasome**. During this process small peptide fragments are formed. These peptides pass into **endoplasmic reticulum (ER)**. In **ER**, the peptide is attached with empty **MHC I** molecule. Then the formed **peptide-MHC I complex** is transported to the cell surface.

On the surface of cell, the **peptide-MHC I complex** is presented to **CD8+ cytotoxic T lymphocytes (CTLs)**. The **CD8+ T cell** recognize the peptide. If the peptide is foreign or abnormal then the T cell is activated. It destroy the infected cell or tumour cell.

**MHC I** also regulate **Natural Killer (NK) cell**. Normal cell shows self peptide by **MHC I** molecule. This gives inhibitory signal to **NK cell** and cell is not killed. When **MHC I** is absent or less on cell surface, **NK cell** identify it as abnormal and kills the cell. This is called **missing self hypothesis**.

## Distribution of Major Histocompatibility Complex I (MHC I)

**Major Histocompatibility Complex class I (MHC I)** is widely distributed in body. It is present on almost all nucleated somatic cells. So most of the body cells show **MHC I** on their surface.

**MHC I** is not found on **RBCs** because mature red blood cells are non-nucleated. But it is present on **platelets**. Platelets are non-nucleated cell fragments, but they carry **MHC I** molecule on their surface.

In **Central Nervous System (CNS)**, **HLA class I antigen** is generally absent or very less. So the cells of brain and spinal cord show poor expression of **MHC I** in normal condition.

The classical **MHC I** molecules are distributed widely. These include **HLA-A**, **HLA-B** and **HLA-C**. They are present on most nucleated cells and help in showing endogenous antigen.

The non-classical **MHC I** molecules have restricted distribution. They are not found in all tissues like classical **MHC I**. Examples are **HLA-G** and **HLA-E**.

**HLA-G** is mainly present on fetal trophoblast cells. These cells are present at maternal-fetal interface. It is also present on thymic epithelium. Thus non-classical **MHC I** has tissue specific distribution.

## Structure of Major Histocompatibility Complex I (MHC I)

![The Membrane-Bound Class I and Class II Major Histocompatibility Complex Molecules – The class I molecule is a heterodimer composed of the alpha protein, which is divided into three domains: α1 , α2 , and α3, and the protein β2 microglobulin (β2 m).](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1559.png)The Membrane-Bound Class I and Class II Major Histocompatibility Complex Molecules – The class I molecule is a heterodimer composed of the alpha protein, which is divided into three domains: α1 , α2 , and α3, and the protein β2 microglobulin (β2 m).

- **Heterodimer**– **MHC I** is a transmembrane heterodimer molecule. It is made up of two different polypeptide chains. One is heavy **alpha (α) chain** and another is small light chain, called **beta-2-microglobulin (β₂m)**. These two chains are joined by non-covalent attachment.

- **Alpha chain**– The heavy **α-chain** is about 45 kDa protein. It is highly polymorphic. In human it is encoded by genes present on chromosome 6. These genes are **HLA-A**, **HLA-B** and **HLA-C**.

- **Membrane part**– The **α-chain** has a hydrophobic transmembrane part. This part passes through the cell membrane. It also has a cytoplasmic tail. The tail remains inside cytoplasm and helps in movement of the molecule inside cell.

- **Outer domains**– The heavy chain has three extracellular domains. These are **α₁**, **α₂** and **α₃**. These domains are present outside the cell. They form the main outer structure of **MHC I** molecule.

- **Peptide platform**– **α₁** and **α₂** domains form the peptide binding platform. They make a groove like area. The floor is formed by eight stranded antiparallel **β-sheet**. The two side walls are formed by **α-helices**.

- **α₃ domain**– **α₃ domain** is present near the membrane. It has immunoglobulin like fold. It binds with **β₂-microglobulin**. It also has the binding site for **CD8** co-receptor of cytotoxic T cell.

- **β₂-microglobulin**– **β₂-microglobulin (β₂m)** is the light chain of **MHC I**. It is about 12 kDa protein. It is invariant and non-polymorphic. In human it is encoded by gene on chromosome 15.

- **Support chain**– **β₂-microglobulin** does not enter into cell membrane. It remains attached with **α₃ domain**. It gives support to **MHC I** molecule. It is needed for proper folding and stability.

- **Binding groove**– The peptide binding groove of **MHC I** is closed at both ends. So long peptide cannot fit in it. It binds short peptide, generally 8 to 11 amino acids.

- **Binding pockets**– The floor of groove has special binding pockets. These are called **A to F pockets**. They bind with anchor residues of peptide. By this way peptide is held tightly in **MHC I** groove.

![Structure of the MHC Class I Protein](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1560.png)Structure of the MHC Class I Protein

## Mechanism of action of Major Histocompatibility Complex I (MHC I)

The following are the steps of mechanism of **Major Histocompatibility Complex class I (MHC I)**–

- **Protein degradation**– In this step, intracellular proteins are broken inside cytoplasm. These proteins may be normal self proteins, viral proteins or tumour antigens. They are degraded by **proteasome**. Small peptide fragments are formed.

- **Peptide transport**– The formed peptides are transported from cytoplasm into **endoplasmic reticulum (ER)**. This transport takes place through **TAP**. **TAP** means **Transporter associated with Antigen Processing**. It is present on **ER** membrane.

- **MHC I assembly**– In **ER**, the heavy **alpha (α) chain** of **MHC I** starts folding. Chaperone protein like **calnexin** helps in this folding. Then the **α-chain** joins with **beta-2-microglobulin (β₂m)**. An empty **MHC I** molecule is formed.

- **Peptide loading complex**– The empty **MHC I** molecule enters into **Peptide Loading Complex (PLC)**. This complex contains **TAP**, **tapasin**, **calreticulin** and **ERp57**. **Tapasin** joins empty **MHC I** with **TAP**. So peptides coming inside **ER** can bind with **MHC I** groove.

- **Peptide trimming**– Some peptides transported by **TAP** are longer in size. These peptides are trimmed by **ERAP** enzyme. Peptides become short, generally 8 to 11 amino acids. This size is suitable for **MHC I** binding groove.

- **Peptide editing**– In this step, proper peptide is selected. **Tapasin** acts like peptide editor. It checks which peptide bind strongly with **MHC I** groove. Weak peptide is removed and strong peptide is kept. **TAPBPR** also helps in this editing process.

- **Stable complex formation**– When a good peptide binds with **MHC I**, the molecule becomes stable. The peptide fits inside the closed groove. Then complete **peptide-MHC I complex** is formed. This complex is released from **PLC**.

- **Surface transport**– The formed **peptide-MHC I complex** comes out from **ER**. It passes through **Golgi apparatus**. Then it reaches to plasma membrane. On the cell surface, it is displayed for immune recognition.

- **CD8 T cell recognition**– On cell surface, **peptide-MHC I complex** is recognized by **CD8+ cytotoxic T lymphocyte (CTL)**. The **T-cell receptor (TCR)** binds with peptide part. **CD8** co-receptor binds with **MHC I** molecule. If the peptide is foreign or abnormal, **CTL** becomes activated.

- **Cell killing**– Activated **CD8+ T cell** kills the infected cell or tumour cell. This killing occur by release of cytotoxic substances. Thus **MHC I** helps in removal of virus infected and malignant cells.

- **NK cell inhibition**– Normal cells show self peptide with **MHC I**. This binds with inhibitory receptor of **Natural Killer (NK) cell**, like **KIR** or **CD94:NKG2A**. It gives do not kill signal. So normal body cell is protected.

- **Missing self**– If **MHC I** is absent or decreased on cell surface, **NK cell** cannot get inhibitory signal. Then **NK cell** identify the cell as abnormal. It may kill that cell. This is called **missing self hypothesis**.

## Deposition of self and non-self peptides in MHC I binding pocket

The following are the steps by which **self** and **non-self peptides** are deposited in **MHC I** binding pocket-

- **Protein source**– The proteins are present inside cytoplasm. These may be normal host protein, called **self protein**. These may also be viral protein, tumour protein or intracellular bacterial protein, called **non-self protein**.

- **Proteasome action**– In cytoplasm, these proteins are degraded by **proteasome**. The protein is cut into small peptide fragments. Both **self** and **non-self peptides** are formed by same process.

- **Peptide transport**– The newly formed peptides are transported into **endoplasmic reticulum (ER)**. This transport is done by **TAP**. **TAP** means **Transporter associated with Antigen Processing**. It takes peptide from cytosol to **ER lumen**.

- **MHC I folding**– In **ER**, the **MHC I alpha chain** starts folding. **Calnexin** and **ERp57** help in this folding. Then **beta-2-microglobulin (β₂m)** binds with alpha chain. An empty **MHC I heterodimer** is formed.

- **PLC formation**– The empty **MHC I** joins with **Peptide Loading Complex (PLC)**. This complex has **TAP**, **tapasin**, **calreticulin** and **ERp57**. **Tapasin** keeps empty **MHC I** near **TAP**. So peptide can directly enter near the binding groove.

- **Groove opening**– **Tapasin** also keeps the peptide binding cleft in open and receptive form. The groove is ready to receive peptide. It does not select self or non-self by name. It selects peptide by proper size and strong fitting.

- **Peptide trimming**– Many peptides coming through **TAP** are longer. The **MHC I** groove is closed at both end. So long peptide cannot fit properly. **ERAP1** trims the peptide and makes it small, generally 8 to 9 amino acids.

- **Peptide loading**– The trimmed peptide enters into **MHC I** binding groove. The peptide binds with different pockets present in the groove. Anchor residues of peptide fit into these pockets. If the fitting is strong then peptide stay in groove.

- **Peptide editing**– **Tapasin** checks the binding of peptide. Weakly bound peptide are removed. Strong peptide are kept. **TAPBPR** can also exchange loose peptide with better binding peptide during transport pathway.

- **Stable complex**– When high affinity peptide binds, the **MHC I** molecule become stable. The peptide is now deposited inside the closed groove. This may be **self peptide** or **non-self peptide**, depending on which protein was degraded inside the cell.

- **Surface display**– The stable **peptide-MHC I complex** leaves **PLC**. It passes through **Golgi apparatus** and reaches plasma membrane. On the cell surface it displays peptide to **CD8+ cytotoxic T lymphocyte**.

- **Recognition**– If the deposited peptide is **self peptide**, usually no cytotoxic response occur. If the peptide is **non-self** or abnormal, **CD8+ T cell** recognize it by **TCR** and the target cell may be killed.

![MHC Peptide-Binding Sites](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1561.png)MHC Peptide-Binding Sites

![Antigen Presentation – Antigens arising from within a cell (including self antigen and those from intracellular pathogens) are degraded by proteasomes and inserted into the antigen-binding pocket of the MHC class I proteins for presentation on the cell surface to a variety of immune cells.](https://biologynotesonline.com/wp-content/uploads/2024/04/image-1562.png)Antigen Presentation – Antigens arising from within a cell (including self antigen and those from intracellular pathogens) are degraded by proteasomes and inserted into the antigen-binding pocket of the MHC class I proteins for presentation on the cell surface to a variety of immune cells.

## Functions of Major Histocompatibility Complex I (MHC I)

The following are the functions of **MHC I**–

- **Antigen presentation**– **MHC I** present intracellular antigen. These antigen are formed inside the cell. It may be self protein, viral protein or tumour protein. These small peptide are shown on cell surface.

- **Endogenous antigen display**– **MHC I** mainly shows endogenous antigen. Endogenous antigen means antigen present inside cytoplasm. So the cell can show its internal protein condition to immune cells.

- **CD8 cell recognition**– The **peptide-MHC I complex** is recognized by **CD8+ cytotoxic T lymphocyte (CTL)**. **TCR** of T cell bind with peptide. **CD8** bind with **MHC I** molecule.

- **Killing of infected cell**– When viral peptide or abnormal peptide is present, **CD8+ T cell** becomes active. It kills the infected cell. It also kill tumour cell. Thus abnormal body cell are removed.

- **Cell mediated immunity**– **MHC I** helps in cell mediated immunity. It does not mainly act by antibody. It acts by activation of **cytotoxic T cell** and destruction of infected cell.

- **NK cell inhibition**– Normal cell has **MHC I** on surface. This **MHC I** bind with inhibitory receptor of **Natural Killer (NK) cell**. Examples are **KIRs** and **CD94:NKG2A**. So **NK cell** get inhibitory signal and does not kill the normal cell.

- **Missing self response**– Some virus infected cell and tumour cell reduce **MHC I** expression. Then **NK cell** cannot get inhibitory signal. The cell is taken as abnormal. This is called **missing self** response. Then **NK cell** kill the cell.

- **NK cell education**– **MHC I** also help in education of **NK cells**. During development, **NK cell** come in contact with self **MHC I**. This makes **NK cell** active but not harmful to normal self cell.

- **Cross presentation**– Some **dendritic cells** can present outside antigen by **MHC I**. This is called cross presentation. It helps in activation of naive **CD8+ T cells** against virus and tumour antigen.

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