HLA-DM

Last updated
major histocompatibility complex, class II, DM alpha
2BC4.pdb1.png
Crystallographic structure of human HLA-DM. [1]
Identifiers
Symbol HLA-DMA
NCBI gene 3108
HGNC 4934
OMIM 142855
RefSeq NM_006120
UniProt P28067
Other data
Locus Chr. 6 p21.3
Search for
Structures Swiss-model
Domains InterPro
major histocompatibility complex, class II, DM beta
Identifiers
Symbol HLA-DMB
NCBI gene 3109
HGNC 4935
OMIM 142856
RefSeq NM_002118
UniProt P28068
Other data
Locus Chr. 6 p21.3
Search for
Structures Swiss-model
Domains InterPro

HLA-DM (human leukocyte antigen DM) is an intracellular protein involved in the mechanism of antigen presentation on antigen presenting cells (APCs) of the immune system. [2] It does this by assisting in peptide loading of major histocompatibility complex (MHC) class II membrane-bound proteins. [3] HLA-DM is encoded by the genes HLA-DMA and HLA-DMB. [4]

Contents

HLA-DM is a molecular chaperone [5] that works in lysosomes and endosomes in cells of the immune system. It works in APCs like macrophages, dendritic cells, and B cells [6] by interacting with MHC class II molecules. [7] HLA-DM protects the MHC class II molecules from breaking down, and regulates which proteins or peptides bind to them as well. [5] This regulates how and when a peptide acts as an antigen initiating an immune response. Thus, HLA-DM is necessary for the immune system to respond effectively to a foreign invader. Impairment in HLA-DM function can result in immunodeficiency and autoimmune diseases. [8]

Genetics

The genes for HLA-DM are located in the MHCII region of the human chromosome 6. [2] The genes code for the alpha and beta chains that make up the protein.

The gene is nonpolymorphic. [8]

Function

HLA-DM transport and functions from the ER to the cell surface of an APC. HLA-DM is synthesized in the endoplasmic reticulum (ER) of antigen presenting cells (APCs), and transported in endosomes while binding to HLA-DO. The HLA-DM containing endosome fuses with an MHC class II containing endosome, which then subsequently fuses with an antigen-containgin endosome. Once in the presence of antigen, HLA-DM associates with MHC class II and releases CLIP from the peptide binding groove. HLA-DO degrades, and HLA-DM facilitates peptide exchange to ensure high affinity binding between the MHC class II and its peptide. The late endosome then fuses with the plasma membrane to present MHC class II + peptide on its surface. This can be recognized by other immune cells and initiate a response. HLA-DM transport and functions from the ER to the cell surface of an APC.jpg
HLA-DM transport and functions from the ER to the cell surface of an APC. HLA-DM is synthesized in the endoplasmic reticulum (ER) of antigen presenting cells (APCs), and transported in endosomes while binding to HLA-DO. The HLA-DM containing endosome fuses with an MHC class II containing endosome, which then subsequently fuses with an antigen-containgin endosome. Once in the presence of antigen, HLA-DM associates with MHC class II and releases CLIP from the peptide binding groove. HLA-DO degrades, and HLA-DM facilitates peptide exchange to ensure high affinity binding between the MHC class II and its peptide. The late endosome then fuses with the plasma membrane to present MHC class II + peptide on its surface. This can be recognized by other immune cells and initiate a response.

MHC class II + peptide interactions

HLA-DM is an integral protein in the mechanism regulating which antigens are presented extracellularly on APCs. It binds partially to the peptide-binding groove of MHC class II molecules. [9] This can affect how well your immune system responds to foreign invaders. [10]

HLA-DM is required to release CLIP from MHC class II molecules, to chaperone empty MHC molecules against denaturation, and to control proper loading and release of peptides at the peptide-binding groove. [11] It also interacts heavily with chaperone protein HLA-DO. [12] All of this ensures proper antigen presentation by an APC, to activate other immune cells. This is critical to rid the body of harmful infections. [13] For example, proper antigen presentation benefits T cell activation, and memory T cell survival and generation. Without it, T cells leaving their site of production and entering the circulatory vessels of the body will not be activated against a danger. [14] The immune system will not be able to kill dangerous or infected cells, and will not react quickly against a second infection.

MHC class II molecule stabilization - chaperonal function

The low pH of lysosomes could cause denaturation or proteolysis of MHC class II molecules. HLA-DM binding to MHC stabilizes and protects from degradation, by covering hydrophobic surfaces. [15] Antigen degradation could also ensue, resulting in an inability to bind to the peptide-binding groove. Thus, HLA-DM is needed to protect proteins against the lysosomal environment. [15]

CLIP release

In order to ensure that no false peptides bind to an MHC class II molecule, the peptide-binding groove is occupied by a protein called CLIP. Once a proper peptide is encountered, HLA-DM catalyzes the exchange of CLIP for an antigen peptide. [16] Often, this peptide is retrieved directly from the B cell receptor which internalized it. Through expulsion of CLIP at the proper time, HLA-DM ensures that the correct antigen can bind to MHC molecules and prevent either from degrading. [13]

Antigen loading and release

Apart from CLIP-antigen exchange, HLA-DM also facilitates antigen-antigen exchange. It releases weakly bound peptides from the groove to load peptides with higher-affinity binding. This process occurs in endosomes once they have left the ER containing MHC and HLA-DM that have fused with antigen-containing lysosomes. [16] Kinetic analysis studies have shown that HLA-DM loading occurs quickly and in many endosomes. Along the membrane of an endosome at the optimal acidity (pH=5.0), HLA-DM loads 3 to 12 peptides onto different MHC molecules per minute. [15]

HLA-DM assists in catalysis of peptide exchange not only in late endosomes traveling from the ER, but also on cell membranes and in early endosomes. Much of this pathway is still being researched, but it is known that HLA-DM can load exogenous peptides onto MHC class II molecules when they are being expressed on cell surfaces. Loading can also occur in early endosomes that are quickly recycled. In both of these areas, loading occurs slower due to an altered pH environment. [6]

Release

To release peptides from the MHC groove, HLA-DM binds to the N terminus of the groove, altering its conformation and breaking hydrogen bonds [2] such that the peptide that was interacting with the MHC groove can no longer bind and is ejected. [8]

Loading

Quick loading of peptides, facilitated by a stable MHC-DM complex, decreases the chances of those peptides being broken down by the proteolytic environment in the endosome. [11] HLA-DM dissociates from the MHC once a stable enough peptide has bound. [15] Thus, only antigens that can "outcompete" others by binding strongly enough to the groove end up on the surface of the antigen presenting cells in MHC class II molecules. [16]

Interaction with HLA-DO

HLA-DM also binds to HLA-DO, another non-classical MHC molecule. HLA-DO starts binding to DM in early endosomes, but is expressed less in late endosomes/lysosomes. [12] The binding between HLA-DM and HLA-DO is less strong at low pH, but overall much stronger than HLA-DM binding to MHC molecules. [14]

Before encountering an antigen, DO acts as a chaperone of DM to stabilize it against denaturation and direct it into lysosomes. It binds in the same location to HLA-DM as MHC class II molecules bind, thereby preventing HLA-DM from binding to MHC class II molecules. This inhibits peptide exchange catalysis and keeps CLIP in the MHC groove [16] until antigen-containing lysosome fuses with DM/DO/MHC containing lysosomes, prompting the degradation of HLA-DO molecules in MIICs. [14]

Structure and binding

HLA-DM contains a N-terminal class II histocompatibility antigen, alpha domain and a C-terminal Immunoglobulin C1-set domain.

Research in crystallography has resulted in advanced knowledge on HLA-DM structure, and how it binds to its substrates (HLA-DO and MHC class II molecules). [9]

HLA-DM Structure

The structure and sequence of HLA-DM proteins is very similar to other MHC class II molecules, [11] all of which consist of a heterodimer composed of an alpha and beta chain. However, HLA-DM differs in that it is nonclassical (meaning it lacks a transport signal N-terminus), and does not have the capability to bind peptides. This is due to lack of a deep peptide binding groove – instead, it contains a shallow, negatively charged indent with two disulfide bonds. [5]

On its beta chain cytoplasmic tail, a tyrosine-based motif YTPL regulates trafficking to specific endosomal compartments called MHC class II compartments (MIICs) from the ER. [2]

Binding with MHC class II

HLA-DM catalyzes peptide exchange through binding at the beta chain of MHC class II molecules, [16] which alters the conformation of the MHC and its peptide-binding groove. HLA-DM conformation stays constant. [17] When a peptide is bound to the P1 locus in the peptide binding groove, it is stably bound. This also hinders HLA-DM binding to the MHC, preventing destabilization of the peptide-MHC interaction. [12] Peptides also bind to the C-terminal site of the binding groove, but in this case the binding is a weak association, leaving the N-terminal of the groove open. HLA-DM can then bind to the N-terminal and allowing for peptide exchange. [12]

Binding with HLA-DO

HLA-DO binds to the same regions of HLA-DM as MHC class II molecules do, such that it blocks the ability of HLA-DM to bind with MHC. [12] Thus, you can never have a complex containing HLA-DM, HLA-DO, and MHC class II molecules.

Expression and Location

Intracellularly, HLA-DM is translated in the endoplasmic reticulum, then transported to endosomal MHC class II compartments (MIICs). MIICs then join with endosomes containing MHC class II molecules bound to CLIP. Here, the HLA-DM begins editing the MHC peptide binding. [2]

HLA-DM is also expressed on the surface of B cells and dendritic cells, [6] as well as in secreted exosomes. [18]

During B cell development, HLA-DM is first expressed in early stages in the bone marrow. Expression then remains high throughout development and a B cell’s life, until the B cell differentiates into a plasma cell and HLA-DM expression then decreases. [14]

Within the body, highest levels of HLA-DM expression is found in lymph nodes, the spleen, and bone marrow. [4]

Role in Disease and Medicine

Immunodeficiency

In individuals lacking functional HLA-DM molecules, improper antigen presentation occurs, resulting in unwanted immune responses or lack of a response when danger is present. [8] This has been shown experimentally through mouse knockout models. [5] There will be an increase of CLIP, instead of peptide, presentation on APC surfaces. This can result in autoimmunity, if a T cell receptors recognize CLIP as a harmful antigen. There could also be no protein presentation at all, resulting in a lack of immune response. [8]

Infections and Disease

Type 1 diabetes is correlated with DM activation, which is hypothesized to be due to DM positively modulating the expression of disease-causing peptides in the MHC groove and thus presented to responding T cells. [12] Experiments using the mouse model of type 1 diabetes which blocked DM or reduced its activity by overexpressing DO found a decrease in diabetes. [12]

HLA-DM is implicated in viral infections like Herpes Simplex Virus Type 1. This virus causes uneven distribution of HLA-DM in endosomes, prevents peptide catalysis, and prevents presentation of MHC class II molecules on the cell surface. [2]

HLA-DM is also implicated in celiac disease, multiple sclerosis, other autoimmune diseases, and leukemia. [6] [19] [20]

Related Research Articles

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Human leukocyte antigen</span> Genes on human chromosome 6

The human leukocyte antigen (HLA) system or complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

Antigen processing, or the cytosolic pathway, is an immunological process that prepares antigens for presentation to special cells of the immune system called T lymphocytes. It is considered to be a stage of antigen presentation pathways. This process involves two distinct pathways for processing of antigens from an organism's own (self) proteins or intracellular pathogens, or from phagocytosed pathogens ; subsequent presentation of these antigens on class I or class II major histocompatibility complex (MHC) molecules is dependent on which pathway is used. Both MHC class I and II are required to bind antigens before they are stably expressed on a cell surface. MHC I antigen presentation typically involves the endogenous pathway of antigen processing, and MHC II antigen presentation involves the exogenous pathway of antigen processing. Cross-presentation involves parts of the exogenous and the endogenous pathways but ultimately involves the latter portion of the endogenous pathway.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

<span class="mw-page-title-main">MHC class I</span> Protein of the immune system

MHC class I molecules are one of two primary classes of major histocompatibility complex (MHC) molecules and are found on the cell surface of all nucleated cells in the bodies of vertebrates. They also occur on platelets, but not on red blood cells. Their function is to display peptide fragments of proteins from within the cell to cytotoxic T cells; this will trigger an immediate response from the immune system against a particular non-self antigen displayed with the help of an MHC class I protein. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called cytosolic or endogenous pathway.

Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present extracellular antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, the result of this process, describes the stimulation of naive cytotoxic CD8+ T cells into activated cytotoxic CD8+ T cells. This process is necessary for immunity against most tumors and against viruses that infect dendritic cells and sabotage their presentation of virus antigens. Cross presentation is also required for the induction of cytotoxic immunity by vaccination with protein antigens, for example, tumour vaccination.

<span class="mw-page-title-main">Antigen presentation</span> Vital immune process that is essential for T cell immune response triggering

Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment can be recognized by a T-cell receptor. Specifically, the fragment, bound to the major histocompatibility complex (MHC), is transported to the surface of the cell, a process known as presentation. If there has been an infection with viruses or bacteria, the cell will present an endogenous or exogenous peptide fragment derived from the antigen by MHC molecules. There are two types of MHC molecules which differ in the behaviour of the antigens: MHC class I molecules (MHC-I) bind peptides from the cell cytosol, while peptides generated in the endocytic vesicles after internalisation are bound to MHC class II (MHC-II). Cellular membranes separate these two cellular environments - intracellular and extracellular. Each T cell can only recognize tens to hundreds of copies of a unique sequence of a single peptide among thousands of other peptides presented on the same cell, because an MHC molecule in one cell can bind to quite a large range of peptides. Predicting which antigens will be presented to the immune system by a certain MHC/HLA type is difficult, but the technology involved is improving.

<span class="mw-page-title-main">MHC class II</span> Protein of the immune system

MHC Class II molecules are a class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells, mononuclear phagocytes, some endothelial cells, thymic epithelial cells, and B cells. These cells are important in initiating immune responses.

<span class="mw-page-title-main">HLA-A</span> Protein-coding gene in the species Homo sapiens

HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I transmembrane proteins. The others are HLA-B and HLA-C. The protein is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is encoded by the B2M gene, which is located at chromosome 15q21.1 in humans.

<span class="mw-page-title-main">CLIP (protein)</span>

CLIP or Class II-associated invariant chain peptide is the part of the invariant chain (Ii) that binds to the peptide binding groove of MHC class II and remains there until the MHC receptor is fully assembled. CLIP is one of the most prevalent self peptides found in the thymic cortex of most antigen-presenting cells. The purpose of CLIP is to prevent the degradation of MHC II dimers before antigenic peptides bind, and to prevent autoimmunity.

<span class="mw-page-title-main">Minor histocompatibility antigen</span>

Minor histocompatibility antigen are peptides presented on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

<span class="mw-page-title-main">Tapasin</span> Type of protein

TAP-associated glycoprotein, also known as tapasin or TAPBP, is a protein that in humans is encoded by the TAPBP gene.

Human leukocyte histocompatibility complex DO (HLA-DO) is an intracellular, dimeric non-classical Major Histocompatibility Complex (MHC) class II protein composed of α- and β-subunits which interact with HLA-DM in order to fine tune immunodominant epitope selection. As a non-classical MHC class II molecule, HLA-DO is a non-polymorphic accessory protein that aids in antigenic peptide chaperoning and loading, as opposed to its classical counterparts, which are polymorphic and involved in antigen presentation. Though more remains to be elucidated about the function of HLA-DO, its unique distribution in the mammalian body—namely, the exclusive expression of HLA-DO in B cells, thymic medullary epithelial cells, and dendritic cells—indicate that it may be of physiological importance and has inspired further research. Although HLA-DM can be found without HLA-DO, HLA-DO is only found in complex with HLA-DM and exhibits instability in the absence of HLA-DM. The evolutionary conservation of both DM and DO, further denote its biological significance and potential to confer evolutionary benefits to its host.

<span class="mw-page-title-main">CD74</span> Mammalian protein found in Homo sapiens

HLA class II histocompatibility antigen gamma chain also known as HLA-DR antigens-associated invariant chain or CD74, is a protein that in humans is encoded by the CD74 gene. The invariant chain is a polypeptide which plays a critical role in antigen presentation. It is involved in the formation and transport of MHC class II peptide complexes for the generation of CD4+ T cell responses. The cell surface form of the invariant chain is known as CD74. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF).

<span class="mw-page-title-main">HLA-F</span> Protein-coding gene in the species Homo sapiens

HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene. It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include IFN-gamma signaling and CDK-mediated phosphorylation and removal of the Saccharomycescerevisiae Cdc6 protein, which is crucial for functional DNA replication.

<span class="mw-page-title-main">HLA-DMB</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DM beta chain is a protein that in humans is encoded by the HLA-DMB gene.

<span class="mw-page-title-main">HLA-DMA</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DM alpha chain is a protein that in humans is encoded by the HLA-DMA gene.

<span class="mw-page-title-main">HLA-DOA</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DO alpha chain is a protein that in humans is encoded by the HLA-DOA gene.

<span class="mw-page-title-main">HLA-DOB</span> Protein-coding gene in the species Homo sapiens

HLA class II histocompatibility antigen, DO beta chain is a protein that in humans is encoded by the HLA-DOB gene.

Immunoevasins are proteins expressed by some viruses that enable the virus to evade immune recognition by interfering with MHC I complexes in the infected cell, therefore blocking the recognition of viral protein fragments by CD8+ cytotoxic T lymphocytes. Less frequently, MHC II antigen presentation and induced-self molecules may also be targeted. Some viral immunoevasins block peptide entry into the endoplasmic reticulum (ER) by targeting the TAP transporters. Immunoevasins are particularly abundant in viruses that are capable of establishing long-term infections of the host, such as herpesviruses.

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