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Ankyrins are a family of proteins that mediate the attachment of
integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a signi ...
s to the
spectrin Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma membr ...
-
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
based membrane cytoskeleton. Ankyrins have binding sites for the beta subunit of spectrin and at least 12 families of integral membrane proteins. This linkage is required to maintain the integrity of the
plasma membrane 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 (t ...
s and to anchor specific
ion channel Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
s, ion exchangers and
ion transporter In biology, a transporter is a transmembrane protein that moves ions (or other small molecules) across a biological membrane to accomplish many different biological functions including, cellular communication, maintaining homeostasis, energy produc ...
s in the plasma membrane. The name is derived from the
Greek Greek may refer to: Greece Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group. *Greek language, a branch of the Indo-European language family. **Proto-Greek language, the assumed last common ancestor ...
word ἄγκυρα (''ankyra'') for "anchor".


Structure

Ankyrins contain four functional domains: an N-terminal domain that contains 24 tandem
ankyrin repeat The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and ''Drosophila'' Notch. Domains consisting of ankyrin tandem repeats mediate prot ...
s, a central domain that binds to
spectrin Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma membr ...
, a death domain that binds to proteins involved in
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, and a C-terminal regulatory domain that is highly variable between different ankyrin proteins.


Membrane protein recognition

The 24 tandem ankyrin repeats are responsible for the recognition of a wide range of membrane proteins. These 24 repeats contain 3 structurally distinct binding sites ranging from repeat 1-14. These binding sites are quasi-independent of each other and can be used in combination. The interactions the sites use to bind to membrane proteins are non-specific and consist of: hydrogen bonding, hydrophobic interactions and electrostatic interactions. These non-specific interactions give ankyrin the property to recognise a large range of proteins as the sequence doesn't have to be conserved, just the properties of the
amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
. The quasi-independence means that if a binding site is not used, it won't have a large effect on the overall binding. These two properties in combination give rise to large repertoire of proteins ankyrin can recognise.


Subtypes

Ankyrins are encoded by three genes (
ANK1 Ankyrin 1, also known as ANK-1, and erythrocyte ankyrin, is a protein that in humans is encoded by the ''ANK1'' gene. Tissue distribution The protein encoded by this gene, Ankyrin 1, is the prototype of the ankyrin family, was first discovered in ...
,
ANK2 Ankyrin-2, also known as Ankyrin-B, and Brain ankyrin, is a protein which in humans is encoded by the ''ANK2'' gene. Ankyrin-2 is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-2 plays an essential role in the localiz ...
and
ANK3 Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ''ANK3'' gene. Function The protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins ANK1 ...
) in mammals. Each gene in turn produces multiple proteins through
alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
.


ANK1

The
ANK1 Ankyrin 1, also known as ANK-1, and erythrocyte ankyrin, is a protein that in humans is encoded by the ''ANK1'' gene. Tissue distribution The protein encoded by this gene, Ankyrin 1, is the prototype of the ankyrin family, was first discovered in ...
gene encodes the AnkyrinR proteins. AnkyrinR was first characterized in human erythrocytes, where this ankyrin was referred to as erythrocyte ankyrin or band2.1. AnkyrinR enables erythrocytes to resist shear forces experienced in the circulation. Individuals with reduced or defective ankyrinR have a form of
hemolytic anemia Hemolytic anemia or haemolytic anaemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular). This most commonly ...
termed
hereditary spherocytosis Hereditary spherocytosis (HS) is a congenital hemolytic disorder, wherein a genetic mutation coding for a structural membrane protein phenotype leads to a spherical shaping of erythrocytic cellular morphology. As erythrocytes are sphere-shaped (sp ...
. In erythrocytes, AnkyrinR links the membrane skeleton to the Cl/HCO3 anion exchanger. Ankyrin 1 links membrane receptor
CD44 The CD44 antigen is a cell-surface glycoprotein involved in cell–cell interactions, cell adhesion and migration. In humans, the CD44 antigen is encoded by the ''CD44'' gene on chromosome 11. CD44 has been referred to as HCAM (homing cell adhes ...
to the
inositol triphosphate receptor Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physiol ...
and the
cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
. It has been suggested that Ankyrin 1 interacts with
KAHRP KAHRP (knob-associated histidine-rich protein) is a protein expressed by ''Plasmodium falciparum'' infecting erythrocytes. KAHRP is a major component of knobs, feature found on Plasmodium falciparum infected erythrocytes. It has been suggested th ...
(shown via selective pull-downs, SPR and
ELISA The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
).


ANK2

Subsequently, ankyrinB proteins (products of the
ANK2 Ankyrin-2, also known as Ankyrin-B, and Brain ankyrin, is a protein which in humans is encoded by the ''ANK2'' gene. Ankyrin-2 is ubiquitously expressed, but shows high expression in cardiac muscle. Ankyrin-2 plays an essential role in the localiz ...
gene) were identified in brain and muscle. AnkyrinB and AnkyrinG proteins are required for the polarized distribution of many membrane proteins including the Na+/K+ ATPase, the voltage gated Na+ channel and the Na+/Ca2+ exchanger.


ANK3

AnkyrinG proteins (products of the
ANK3 Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ''ANK3'' gene. Function The protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins ANK1 ...
gene) were identified in epithelial cells and neurons. A large-scale genetic analysis conducted in 2008 shows the possibility that
ANK3 Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ''ANK3'' gene. Function The protein encoded by this gene, ankyrin-3 is an immunologically distinct gene product from ankyrins ANK1 ...
is involved in
bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
.


See also

*
DARPin DARPins (an acronym for designed ankyrin repeat proteins) are genetically engineered antibody mimetic proteins typically exhibiting highly specific and high-affinity target protein binding. They are derived from natural ankyrin repeat proteins, on ...
(designed ankyrin repeat protein), an engineered antibody mimetic based on the structure of ankyrin repeats


References


External links

* * Ankyrin-R {{Cytoskeletal proteins Peripheral membrane proteins Biology of bipolar disorder it:Anchirina