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MHC class I

 

 
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MHC class I
 
 
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There are two primary classes of major histocompatibility complex
Major histocompatibility complex

The major histocompatibility complex is a large genome region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system, autoimmunity, and reproduction success....
 (MHC) molecules, class I and MHC class II
MHC class II

MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
. MHC class I molecules are found on almost every nucleated cell of the body. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.

class I molecules are heterodimers, consisting of a single transmembrane
Transmembrane protein

A transmembrane protein is a protein that spans the entire biological membrane. Transmembrane proteins aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them can be also extracted using denaturing agents....
 polypeptide chain (the a-chain) and a ß2 microglobulin
Beta-2 microglobulin

?2 microglobulin also known as B2M is a component of MHC class I molecules, which are present on almost all cells of the body ....
 (which is encoded elsewhere, not in the MHC).






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There are two primary classes of major histocompatibility complex
Major histocompatibility complex

The major histocompatibility complex is a large genome region or gene family found in most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important role in the immune system, autoimmunity, and reproduction success....
 (MHC) molecules, class I and MHC class II
MHC class II

MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
. MHC class I molecules are found on almost every nucleated cell of the body. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.

Structure

MHC class I molecules are heterodimers, consisting of a single transmembrane
Transmembrane protein

A transmembrane protein is a protein that spans the entire biological membrane. Transmembrane proteins aggregate and precipitate in water. They require detergents or nonpolar solvents for extraction, although some of them can be also extracted using denaturing agents....
 polypeptide chain (the a-chain) and a ß2 microglobulin
Beta-2 microglobulin

?2 microglobulin also known as B2M is a component of MHC class I molecules, which are present on almost all cells of the body ....
 (which is encoded elsewhere, not in the MHC). The a chain has three polymorphic domains, a1, a2, a3. Between a1 and a2 is the peptide-binding groove which binds peptides derived from cytosol
Cytosol

The cytosol or intracellular fluid is the liquid found inside cell . In eukaryotes this liquid is separated by cell membranes from the contents of the organelles suspended in the cytosol, such as the mitochondrial matrix inside the mitochondrion....
ic proteins. The groove consists of eight ß-pleated sheets on the bottom and two a helices making up sides. The peptide in the groove remains bound for the life of the class I molecule, and is typically 8-9 amino acids in length.

CD8 molecule binds to a3 fragment.

Production

The peptides are mainly generated in the cytosol
Cytosol

The cytosol or intracellular fluid is the liquid found inside cell . In eukaryotes this liquid is separated by cell membranes from the contents of the organelles suspended in the cytosol, such as the mitochondrial matrix inside the mitochondrion....
 by the proteasome
Proteasome

Proteasomes are large protein complexes inside all eukaryotes and archaea, as well as in some bacteria. In eukaryotes, they are located in the cell nucleus and the cytoplasm....
. The proteasome is a macromolecule that consists of 28 subunits, of which half affect proteolytic
Proteolysis

Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion....
 activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. The peptides have to be translocated from the cytosol into the endoplasmic reticulum
Endoplasmic reticulum

The endoplasmic reticulum is a eukaryote organelle that forms an interconnected network of tubules, vesicle , and cisternae within cell . The lacey membranes of the endoplasmic reticulum were first seen by Keith R....
 (ER) to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER.

Translocation

The peptide translocation from the cytosol into the lumen of the ER is accomplished by the transporter associated with antigen processing
Transporter associated with antigen processing

Transporter associated with antigen processing is a member of the ATP-binding cassette transporter. It delivers cytosolic peptides into the endoplasmic reticulum , where they bind to nascent MHC class I molecules....
 (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. The two subunits form a peptide binding site and two ATP binding sites that face the lumen of the cytosol. TAP binds peptides on the cytoplasmic site and translocates them under ATP
Adenosine triphosphate

This article is about the chemical used by cells as an energy carrier. For other uses, see ATP .Adenosine-5'-triphosphate is a multifunctional nucleotide, and plays an important role in cell biology as a coenzyme that is the "molecule unit of currency" of intracellular energy transfer....
 consumption into the lumen of the ER. The MHC class I molecule is then in turn loaded with peptides in the lumen of the ER. The peptide-loading process involves several other molecules that form a large multimeric complex consisting of TAP, tapasin
Tapasin

TAP binding protein , also known as TAPBP, is encoded for by a human gene.Tapasin is a MHC class I antigen processing molecule present in the lumen of the endoplasmic reticulum....
, calreticulin
Calreticulin

Calreticulin is a multifunctional protein that binds calcium ions , rendering it inactive. The Ca2+ is bound with low Chemical affinity, but high capacity, and can be released on a signal ....
, calnexin
Calnexin

Calnexin is a 90kDa integral protein of the endoplasmic reticulum . It consists of a large N-terminal calcium-Binding Lumen protein domain, a single transmembrane helix and a short , acidic cytoplasmic tail....
, and ERP57.

Once the peptide is loaded onto the MHC class I molecule, it leaves the ER through the secretory pathway
Secretory pathway

The secretory pathway is a series of steps a Cell uses to move proteins out of the cell; a process known as secretion. The path of a protein destined for secretion has its origins in the rough endoplasmic reticulum, a membrane bound Cellular_compartment in the cell....
 to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modification
Posttranslational modification

Posttranslational modification is the chemistry modification of a protein after its translation . It is one of the later steps in protein biosynthesis for many proteins....
s of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan regions of the protein, followed by extensive changes to the N-glycans in the Golgi apparatus
Golgi apparatus

The Golgi apparatus is an organelle found in most eukaryote Cell . It was identified in 1898 by the Italian physician Camillo Golgi and was named after him....
. The N-glycans mature fully before they reach the cell surface.

Peptide removal

Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum are removed from the ER via the sec61
Sec61

Sec61 is an endoplasmic reticulum membrane protein translocator . It is a doughnut shaped pore through the membrane with 3 major subunits . It has a region called the plug that blocks transport into or out of the ER....
 channel into the cytosol, where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to an MHC class I molecule.

For example, an interaction of sec61 with bovine albumin
Albumin

Albumin refers generally to any protein with water solubility, which is moderately soluble in concentrated salt solutions, and experiences heat Denaturation ....
 has been observed.

Effect of viruses

MHC class I molecules are loaded with proteins generated in the cytosol. As viruses infect a cell by entering its cytoplasm, this cytosolic, MHC class I-dependent pathway of antigen presentation is the primary way for a virus-infected cell to signal T cell
T cell

T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells by the presence of a special receptor on their cell surface called T cell receptors ....
s.

MHC class I molecules generally interact with CD8+ ("cytotoxic") T cells (CTLs)
Cytotoxic T cell

A cytotoxic T cell belongs to a sub-group of T cells that are capable of inducing the death of infection somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or dysfunctional....
.

The fate of the virus-infected cell is almost always apoptosis
Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed Cell death involves a series of biochemical events leading to a characteristic cell Morphology and death, in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including Bleb , changes...
 initiated by the CTL, effectively reducing the risk of infecting neighboring cells.

Genes and isotypes

  • Very polymorphic
  • (HLA-A
    HLA-A

    HLA-A are a group of human leukocyte antigens that are wikt:encode by the HLA-A locus on human chromosome 6p. The HLA genes constitute the major histocompatibility gene complex of human....
    )
  • (HLA-B
    HLA-B

    HLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex....
    )
  • (HLA-C
    HLA-C

    HLA-C belongs to the MHC class I heavy chain receptors. The C receptor is a heterodimer consisting of a HLA-C mature gene product and ?2-microglobulin....
    )


  • Less polymorphic
  • (HLA-E)
  • (HLA-F
    HLA-F

    Major histocompatibility complex, class I, F, also known as HLA-F, is a human gene.ReferencesFurther reading...
    )
  • (HLA-G
    HLA-G

    HLA-G histocompatibility antigen, class I, G, also known as HLA-G, or Human Leukocyte Antigen G, is a human gene....
    )*


Additional images


External links