Influenza
hemagglutinin (HA) or
haemagglutinin (
British EnglishBritish English, or UK English or English 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
hemagglutininInfluenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein...
found on the surface of the
influenzaInfluenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals. The name influenza is Italian and means "influence"...
virusA virus is an infectious agent too small to be seen directly with a light microscope. They are not made of cells and can only replicate inside the cells of another organism . Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es. It is an
antigenAn antigen is a substance that prompts the generation of antibodies and can cause an immune response. "Self" antigens are usually tolerated by the immune system; whereas "Non-self" antigens are identified as intruders and attacked by the immune system...
ic
glycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to their 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
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, 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.
The name "hemagglutinin" comes from the
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
's ability to cause red blood cells (erythrocytes) to clump together ("
agglutinateAgglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare, meaning "to glue to."This occurs in biology in three main examples:...
")
in vitro .
There are at least 16 different HA antigens.
Influenza
hemagglutinin (HA) or
haemagglutinin (
British EnglishBritish English, or UK English or English 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
hemagglutininInfluenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein...
found on the surface of the
influenzaInfluenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals. The name influenza is Italian and means "influence"...
virusA virus is an infectious agent too small to be seen directly with a light microscope. They are not made of cells and can only replicate inside the cells of another organism . Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
es. It is an
antigenAn antigen is a substance that prompts the generation of antibodies and can cause an immune response. "Self" antigens are usually tolerated by the immune system; whereas "Non-self" antigens are identified as intruders and attacked by the immune system...
ic
glycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to their 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
cellThe cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of an organism that is classified as living, 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.
The name "hemagglutinin" comes from the
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
's ability to cause red blood cells (erythrocytes) to clump together ("
agglutinateAgglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare, meaning "to glue to."This occurs in biology in three main examples:...
")
in vitro .
Subtypes
There are at least 16 different HA antigens. These subtypes are labeled H1 through H16. The last, H16, was discovered only recently on influenza A viruses isolated from black-headed
gullGulls 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
SwedenSweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe...
and
NorwayNorway , officially the Kingdom of Norway, is a country in Northern Europe occupying the western portion of the Scandinavian Peninsula, as well as Jan Mayen and the Arctic archipelago of Svalbard under the Spitsbergen Treaty...
. The first three hemagglutinins, H1, H2, and H3, are found in
humanHumans are bipedal primates belonging to the species Homo sapiens in Hominidae, the great ape family. They are the only surviving member of the genus Homo. Humans have a highly developed brain, capable of abstract reasoning, language, introspection, and problem solving...
influenza viruses.
A highly pathogenic avian flu virus of
H5N1Influenza 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 acidAmino acids are molecules containing an amine group, a carboxylic acid group and one of the twenty R-groups. These molecules are particularly important in biochemistry, where this term refers to alpha-amino acids with the general formula H
2NCHRCOOH, where R is an organic substituent...
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
proteolysisA protease breaks down proteins. 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 mechanisms of action
HA has two primary functions:
- allowing the recognition of target vertebrate
Vertebrates are members of the subphylum Vertebrata, chordates with backbones or spinal columns. About 58,000 species of vertebrates have been described. Vertebrata is the largest subphylum of chordates, and contains many familiar groups of large land animals. Vertebrates comprise cyclostomes, bony...
cells, accomplished through the binding of these cells' sialic 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...
-containing receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
s, and
- allowing the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane.
Mechanism
HA binds to the monosaccharide sialic acid which is present on the surface of its target cells. This 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
endosomeIn biology, an endosome is a membrane-bound compartment inside cells, roughly 500 nm in diameter when fully mature.-Function:Many endocytotic vesicles, derived from the plasma membrane, are either transported to a pre-existing endosome and fuse with it or are acidified via proton pump to become an...
, 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
lysosomethumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s:
[[nucleolus]]
[[cell nucleus|nucleus]]
[[ribosomes]]
[[vesicle |vesicle]]
...
. 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
PDB molecule of the month: Hemagglutinin (April 2006))
Structure
HA is a homotrimeric integral membrane
glycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to their 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
cylinderA cylinder is one of the most basic curvilinear geometric shapes, the surface formed by the points at a fixed distance from a given straight line, 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
monomerA monomer is a small molecule that may become chemically bonded to other monomers to form a polymer...
s that constitute HA are constructed into a central
α helixA common motif in the secondary structure of proteins, the alpha helix is a right- or left-handed coiled conformation, resembling a spring, 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 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...
binding sites. HA monomers are synthesized as
precursorA 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
glycosylatedGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
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.
See also
- Phytohemagglutinin
- Hemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein...
- Neuraminidase
Neuraminidase enzymes are glycoside hydrolase enzymes which 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 influenza...
- Antigenic shift
Antigenic shift is the process by which at least two different strains of a virus , especially influenza, combine to form a new subtype having a mixture of the surface antigens of the two original strains. The term antigenic shift is more often applied specifically to the influenza literature, as...
- 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...
- Epitope
An epitope, also known as antigenic determinant, is the part of a macromolecule 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 structure
H5N1 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