Hemagglutinin
Encyclopedia
Influenza hemagglutinin (HA) or haemagglutinin (British English
) is a type of hemagglutinin
found on the surface of the influenza
virus
es. It is an antigen
ic glycoprotein
. It is responsible for binding the virus to the cell
that is being infected. HA proteins bind to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes.
The name "hemagglutinin" comes from the protein
's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate
") in vitro.
There are at least 16 different HA antigens. These subtypes are named H1 through H16. The last, H16, was discovered only in 2004 on influenza A viruses isolated from black-headed gull
s from Sweden
and Norway
. The first three hemagglutinins, H1, H2, and H3, are found in human
influenza viruses.
Viral neuraminidase
(NA) is another protein found on the surface of influenza. Influenza viruses are characterised by the type of HA and NA that they carry; hence H1N1, H5N2 etc.
A highly pathogenic avian flu virus of H5N1
type has been found to infect humans at a low rate. It has been reported that single amino acid
changes in this avian virus strain's type H5 hemagglutinin have been found in human patients that "can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses". This finding seems to explain how an H5N1 virus that normally does not infect humans can mutate and become able to efficiently infect human cells. The hemagglutinin of the H5N1 virus has been associated with the high pathogenicity of this flu virus strain, apparently due to its ease of conversion to an active form by proteolysis
.
cells, accomplished through the binding of these cells' sialic acid
-containing receptor
s. Secondly, once bound it facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane.
HA binds to the monosaccharide sialic acid which is present on the surface of its target cells, which causes the viral particles to stick to the cell's surface. The cell membrane then engulfs the virus and the portion of the membrane that encloses it pinches off to form a new membrane-bound compartment within the cell called an endosome
, which contains the engulfed virus. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome
. However, as soon as the pH within the endosome drops to about 6.0, the original folded structure of the HA molecule becomes unstable, causing it to partially unfold, and releasing a very hydrophobic portion of its peptide chain that was previously hidden within the protein.
This so-called "fusion peptide" acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, when the rest of the HA molecule refolds into a new structure (which is more stable at the lower pH), it "retracts the grappling hook" and pulls the endosomal membrane right up next to the virus particle's own membrane, causing the two to fuse together. Once this has happened, the contents of the virus, including its RNA genome, are free to pour out into the cell's cytoplasm. (see Molecule of the Month at the RCSB Protein Data Bank: Hemagglutinin (April 2006))
HA is a homotrimeric integral membrane glycoprotein
. It is shaped like a cylinder
, and is approximately 13.5 nanometres long. The three identical monomer
s that constitute HA are constructed into a central α helix
coil; three spherical heads contain the sialic acid
binding sites. HA monomers are synthesized as precursor
s that are then glycosylated
and cleaved into two smaller polypeptides: the HA1 and HA2 subunits. Each HA monomer consists of a long, helical chain anchored in the membrane by HA2 and topped by a large HA1 globule.
. Neutralizing antibodies
against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin:
Most commonly, antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure at right) and physically block the interaction with sialic acid
receptors on target cells. In contrast, some antibodies have been found to have no effect on attachment. Instead, this latter group of antibodies acts by preventing membrane fusion. Most of these antibodies, like the human antibody CR6261
, recognize sites in the stem/stalk region region (orange region in figure at right), far away from the receptor binding site The stem (also called HA2), contains most of the membrane fusion machinery of the hemagglutinin protein, and antibodies targeting this region block key structural changes that drive the membrane fusion process. However, at least one fusion-inhibiting antibody
was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process.
British English
British English, or English , is the broad term used to distinguish the forms of the English language used in the United Kingdom from forms used elsewhere...
) is a type of hemagglutinin
Hemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
found on the surface of the influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...
virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es. It is an antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
. It is responsible for binding the virus to the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
that is being infected. HA proteins bind to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes.
The name "hemagglutinin" comes from the protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate
Agglutination (biology)
Agglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare, meaning "to glue."This occurs in biology in three main examples:...
") in vitro.
Subtypes
Gull
Gulls are birds in the family Laridae. They are most closely related to the terns and only distantly related to auks, skimmers, and more distantly to the waders...
s from Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
and Norway
Norway
Norway , officially the Kingdom of Norway, is a Nordic unitary constitutional monarchy whose territory comprises the western portion of the Scandinavian Peninsula, Jan Mayen, and the Arctic archipelago of Svalbard and Bouvet Island. Norway has a total area of and a population of about 4.9 million...
. The first three hemagglutinins, H1, H2, and H3, are found in human
Human
Humans are the only living species in the Homo genus...
influenza viruses.
Viral neuraminidase
Viral neuraminidase
Viral neuraminidase is a type of neuraminidase found on the surface of influenza viruses that enables the virus to be released from the host cell...
(NA) is another protein found on the surface of influenza. Influenza viruses are characterised by the type of HA and NA that they carry; hence H1N1, H5N2 etc.
A highly pathogenic avian flu virus of H5N1
H5N1
Influenza A virus subtype H5N1, also known as "bird flu", A or simply H5N1, is a subtype of the influenza A virus which can cause illness in humans and many other animal species...
type has been found to infect humans at a low rate. It has been reported that single amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
changes in this avian virus strain's type H5 hemagglutinin have been found in human patients that "can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses". This finding seems to explain how an H5N1 virus that normally does not infect humans can mutate and become able to efficiently infect human cells. The hemagglutinin of the H5N1 virus has been associated with the high pathogenicity of this flu virus strain, apparently due to its ease of conversion to an active form by proteolysis
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....
.
Functions and Mechanism
HA has two functions. Firstly, it allows the recognition of target vertebrateVertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
cells, accomplished through the binding of these cells' sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
-containing receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s. Secondly, once bound it facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane.
HA binds to the monosaccharide sialic acid which is present on the surface of its target cells, which causes the viral particles to stick to the cell's surface. The cell membrane then engulfs the virus and the portion of the membrane that encloses it pinches off to form a new membrane-bound compartment within the cell called an endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...
, which contains the engulfed virus. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
. However, as soon as the pH within the endosome drops to about 6.0, the original folded structure of the HA molecule becomes unstable, causing it to partially unfold, and releasing a very hydrophobic portion of its peptide chain that was previously hidden within the protein.
This so-called "fusion peptide" acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, when the rest of the HA molecule refolds into a new structure (which is more stable at the lower pH), it "retracts the grappling hook" and pulls the endosomal membrane right up next to the virus particle's own membrane, causing the two to fuse together. Once this has happened, the contents of the virus, including its RNA genome, are free to pour out into the cell's cytoplasm. (see Molecule of the Month at the RCSB Protein Data Bank: Hemagglutinin (April 2006))
Structure
(more details...)HA is a homotrimeric integral membrane glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
. It is shaped like a cylinder
Cylinder (geometry)
A cylinder is one of the most basic curvilinear geometric shapes, the surface formed by the points at a fixed distance from a given line segment, the axis of the cylinder. The solid enclosed by this surface and by two planes perpendicular to the axis is also called a cylinder...
, and is approximately 13.5 nanometres long. The three identical monomer
Monomer
A monomer is an atom or a small molecule that may bind chemically to other monomers to form a polymer; the term "monomeric protein" may also be used to describe one of the proteins making up a multiprotein complex...
s that constitute HA are constructed into a central α helix
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
coil; three spherical heads contain the sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
binding sites. HA monomers are synthesized as precursor
Protein precursor
A protein precursor, also called a pro-protein or pro-peptide, is an inactive protein that can be turned into an active form by posttranslational modification. The name of the precursor for a protein is often prefixed by pro...
s that are then glycosylated
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
and cleaved into two smaller polypeptides: the HA1 and HA2 subunits. Each HA monomer consists of a long, helical chain anchored in the membrane by HA2 and topped by a large HA1 globule.
Neutralizing Antibodies
Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodiesNeutralizing antibody
A Neutralizing antibody, or NAb is an antibody which defends a cell from an antigen or infectious body by inhibiting or neutralizing any effect it has biologically...
. Neutralizing antibodies
Neutralizing antibody
A Neutralizing antibody, or NAb is an antibody which defends a cell from an antigen or infectious body by inhibiting or neutralizing any effect it has biologically...
against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin:
- Inhibition of attachmentVirusA virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
to target cells - Inhibition of membrane fusion (entry)
Most commonly, antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure at right) and physically block the interaction with sialic acid
Sialic acid
Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
receptors on target cells. In contrast, some antibodies have been found to have no effect on attachment. Instead, this latter group of antibodies acts by preventing membrane fusion. Most of these antibodies, like the human antibody CR6261
CR6261
CR6261 is a monoclonal antibody that binds to a broad range of the influenza virus including the 1918 "Spanish flu" and to a virus of the H5N1 class of avian influenza that jumped from chickens to a human in Vietnam in 2004...
, recognize sites in the stem/stalk region region (orange region in figure at right), far away from the receptor binding site The stem (also called HA2), contains most of the membrane fusion machinery of the hemagglutinin protein, and antibodies targeting this region block key structural changes that drive the membrane fusion process. However, at least one fusion-inhibiting antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process.
See also
- F16 antibody
- Phytohemagglutinin
- HemagglutininHemagglutininInfluenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
- NeuraminidaseNeuraminidaseNeuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
- Antigenic shiftAntigenic shiftAntigenic shift is the process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains...
- Sialic acidSialic acidSialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
- EpitopeEpitopeAn epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
- H5N1 genetic structureH5N1 genetic structureH5N1 genetic structure is the molecular structure of the H5N1 virus's RNA.H5N1 is an Influenza A virus subtype. Experts believe it might mutate into a form that transmits easily from person to person...
Further reading
- Jmol tutorial of influenza hemagglutinin structure and activity. (April 2006)
- Influenza Research Database Database of influenza protein sequences and structures