HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''HLA-E''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. The human HLA-E is a non-classical

MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules (the other being MHC class II) and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on plat ...

molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called

Qa-1b Within molecular and cell biology, Qa-1b is a MHC class I molecule and is the functional homolog of HLA-E in humans. Qa-1b is characterised by its limited polymorphisms and small peptide repertoire. Qa-1b binds to peptides derived from signal p ...

, officially known as H2-T23.

Structure

Like other

molecules, HLA-E is a heterodimer consisting of an α heavy chain and a light chain ( β-2 microglobulin). The heavy chain is approximately 45 kDa and anchored in the membrane. The HLA-E gene contains 8

exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

. Exon one encodes the

signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-ter ...

, exons 2 and 3 encode the α1 and α2 domains, which both bind the peptide, exon 4 encodes the α3 domain, exon 5 encodes the

transmembrane domain A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bil ...

, and exons 6 and 7 encode the cytoplasmic tail.

Function

HLA-E has a very specialized role in cell recognition by

natural killer cells Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

(NK cells). HLA-E binds a restricted subset of peptides derived from

signal peptides A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16-30 amino acids long) present at the N-te ...

of classical MHC class I molecules, namely HLA-A, B, C, G. These peptides are released from the membrane of the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER) by the

signal peptide peptidase In molecular biology, the Signal Peptide Peptidase (SPP) is a type of protein that specifically cleaves parts of other proteins. It is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in adjacent transmemb ...

and trimmed by the cytosolic

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

. Upon transport into the ER lumen by the

transporter associated with antigen processing Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules. ...

(TAP), these peptides bind to a peptide binding groove on the HLA-E molecule. This allows HLA-E to assemble correctly and to be expressed on the

cell surface The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

. NK cells recognize the HLA-E+peptide complex using the heterodimeric receptor

CD94 CD94 (Cluster of Differentiation 94), also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human gene. The protein encoded by CD94 gene is a lectin, cluster of differentiation and a receptor that is involved in cell s ...

NKG2 NKG2 also known as CD159 (Cluster of Differentiation 159) is a receptor for natural killer cells (NK cells). There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to mak ...

A/B/C. When CD94/NKG2A or CD94/NKG2B is engaged, it produces an inhibitory effect on the cytotoxic activity of the NK cell to prevent cell lysis. However, binding of HLA-E to CD94/NKG2C (see KLRC2) results in NK cell activation. This interaction has been shown to trigger expansion of NK cell subsets in antiviral responses, where adaptive NK cells that express CD94/NKG2C can specifically recognise

HCMV ''Human betaherpesvirus 5'', also called human cytomegalovirus (HCMV), is species of virus in the genus ''Cytomegalovirus'', which in turn is a member of the viral family known as ''Herpesviridae'' or herpesviruses. It is also commonly called ...

-derived peptide antigens.

Structure

Function

References

Further reading