Ankyrin

Ankyrins are a family of proteins called repeat proteins that contain ankyrin-like repeats in their structure. Proteins in which ankyrin repeats are present are binding proteins that interact with integral membrane proteins via dynamic non-covalent bonds and help determine their distribution within the cell membrane. They play a key role in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains.

Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing several ankyrin repeats, a central region with a highly conserved spectrin-binding domain and a carboxy-terminal regulatory domain, which is the least conserved and subject to variation.

Multiple isoforms of ankyrin are now known with different affinities for different target proteins. They are expressed in a tissue-specific, developmentally regulated manner. In erythrocytes, for example, ankyrin binds to the cell membrane via spectrin (Michaely P et al. 2002).

The sarcoplasmic small ankyrin 1 protein (sANK1) interacts with connectin (titin) and thereby positions the sarcoplasmic reticulum (SR) at the Z-disc of the sarcomere. Titin is the largest protein in mammals with up to 3.7 MDa and forms the third filament system in cardiac and skeletal muscle alongside actin and myosin. This documents the important physiological role of sANK1.

The pathogen Plasmodium falciparum also binds to ankyrin.

Specific ankyrin antibodies bind to a Treponema pallidum acidic repeat protein and are used to detect Treponema pallidum.

Mutations in genes encoding ankyrin-like proteins can cause defects in gene expression that lead to the onset and progression of some human and animal diseases. For example, half of the cases of "hereditary spherocytosis" are based on a mutation (deletion) in the ankyrin gene (Agarwal AM (2019). The genetic defect in ankyrin on the inside of the erythrocyte membrane leads to reduced membrane stability. The reduced membrane stability leads to reduced osmotic resistance of the erythrocytes. This leads to increased degradation in the spleen with hemolytic anemia and splenomegaly

In some forms (around 2%) of dilated cardiomyopathy, mutated proteins with "ankyrin repeats" have also been detected in their structure. The ankyrin repeat domain 1 gene (ANKRD1) was identified as a disease gene in 2009. The gene codes for the cardiac ankyrin repeat protein (CARP) with a molecular weight of approximately 36 kDa. Three different, functionally intact mRNA transcripts of ANKRD-1 are known and are translated: ankrd1 - ankrd3. However, the functional significance of the variants is still unclear.

ANK-1 is a putative immunogenic antigen epitope and has 100 % identity to an immunogenic SARS-CoV-2 surface glycoprotein called spike protein. The immunogenic epitope is also found on B cells. Thus, the viral spike glycoprotein encoded by mRNA vaccines could induce the production of antibodies against the spike protein, which could cross-react with the ANK-1 RBC protein by molecular mimicry and lead to AIHA (Angileri F et al. (2020) Is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with COVID-19? Br J Haematol 190:e92-e93.

1. Agarwal AM (2019) Ankyrin Mutations in Hereditary Spherocytosis. Acta Haematol 141:63-64

2. Angileri F et al. (2020) Is molecular mimicry the culprit in the autoimmune haemolytic anaemia affecting patients with COVID-19? Br J Haematol 190:e92-e93.

3. Michaely P et al. (2002)Crystal structure of a 12 ANK repeat stack from human ankyrinR. In: The EMBO Journal. 21: 6387-6396