Disease relevance of ANK1

• Close linkage of the gene for Werner's syndrome to ANK1 and D8S87 on the short arm of chromosome 8 [1].
• Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8 [2].
• Vaccinia virus (VV) K1L is a host-range gene and encodes a protein comprised of six ankyrin repeats (ANKs) [3].
• We identify a human mutation (E1053K) in the ankyrin-binding motif of Na(v)1.5 that is associated with Brugada syndrome, a fatal cardiac arrhythmia caused by altered function of Na(v)1 [4].
• The phosphorylation state of the conserved FIGQY tyrosine in the cytoplasmic domain of neurofascin regulates ankyrin binding and governs neurofascin-dependent cell aggregation as well as cell sorting when neurofascin is expressed in neuroblastoma cells [5].

High impact information on ANK1

• Examples are ankyrin-dependent targeting of proteins to excitable membrane domains in the plasma membrane and the Ca(2+) homeostasis compartment of the endoplasmic reticulum [6].
• However, completion of the genomes of simple metazoans and application of homologous recombination in mice now are providing the first glimpses of the full scope of physiological roles for spectrin, ankyrin, and their associated proteins [6].
• Interaction occurred between the carboxy-terminal domain of schwannomin isoform 2 and the ankyrin-binding region of betaII-spectrin [7].
• The position of the sixth ankyrin repeat shows that full-length IkappaBalpha will occlude the NF-kappaB DNA-binding cleft [8].
• Ankyrin-1 mutations are a major cause of dominant and recessive hereditary spherocytosis [9].

Chemical compound and disease context of ANK1

• Arpp, a protein containing an ankyrin repeat domain, PEST sequence, and proline-rich region, is a novel ankyrin-repeated protein highly homologous to Carp, which is proposed to be the putative genetic marker for cardiac hypertrophy [10].
• Growth of Escherichia coli in acetate as a sole carbon source is inhibited by ankyrin-like repeats present in the 2',5'-linked oligoadenylate-dependent human RNase L enzyme [11].

Biological context of ANK1

• The WRN locus was mapped relative to the marker loci, PLAT, ANK1, D8S135, and D8S87 of the comprehensive chromosome 8 linkage map [12].
• The markers, their maximum lod scores, and recombination distances were ANK1 (ankyrin)--2.0 at 16%; D8S5 (TL11)--5.3 at 17%; D8S87 [a(CA)n repeat]--7.2 at 14%; LPL (lipoprotein lipase)--1.5 at 26%; and PLAT (plasminigen activator, tissue)--10.6 at 7% [13].
• Nor did it show any alteration in the exons of the two ANK1 alleles, and the aggravating factor remained elusive [14].
• Ankyrin Napoli: a de novo deletional frameshift mutation in exon 16 of ankyrin gene (ANK1) associated with spherocytosis [15].
• In the DNA of peripheral blood mononuclear cells from healthy individuals, the promoter regions of EPB3 and ELB42 were extensively methylated, but the SPTB and ANK1 promoters were totally unmethylated [16].

Anatomical context of ANK1

• The association of ankyrin with the AE1 anion exchanger contributes an essential function to the mechanical and viscoelastic properties of the erythrocyte and constitutes the best understood link between the plasma membrane and the underlying membrane skeleton [17].
• Ankyrin and synapsin: spectrin-binding proteins associated with brain membranes [18].
• The observations that some residues of the ankyrin binding site are mutated in Rh and RhAG proteins from some weak D and Rh(null) variants, respectively, suggest that the Rh-RhAG/ankyrin-R interaction plays a crucial role in the biosynthesis and/or the stability of the Rh complex in the red cell membrane [19].
• The erythrocyte membrane provides the best studied example of how the spectrin-actin based membrane cytoskeleton is linked via two proteins, ankyrin and protein 4.1, to the anion exchanger (anion exchanger 1, AE1) [20].
• We report here that ank1.5, a small splice variant of the ank1 gene localized on the sarcoplasmic reticulum membrane, is capable of interacting with a sequence of 25 aa located at the COOH terminus of obscurin [21].

Associations of ANK1 with chemical compounds

• The 89 kDa NH2-terminal domain of erythrocyte ankyrin is composed almost entirely of 22 tandem repeats of a 33 amino acid sequence and constitutes the binding site for the cytoplasmic NH2-terminal domain of the erythrocyte anion exchanger, AE1 [22].
• Mass spectrometric analysis of the hydrolysis products showed that FP-2-mediated cleavage of ankyrin occurred immediately after arginine 1,210 [23].
• A cysteine protease activity from Plasmodium falciparum cleaves human erythrocyte ankyrin [24].
• The polymer experiments showed the presence of spectrin, ankyrin, Band 3, Band 4.1, glucose transporter, actin and haemoglobin epitopes in the polymer (Mr 3.10(6)-5.10(6] [25].
• The optimal activity of the purified enzyme, using ankyrin as substrate, was observed at pH 7.0-7.5, and the activity was strongly inhibited by standard inhibitors of cysteine proteinases (cystatin, NEM, leupeptin, E-64 and MDL 28 170), but not by inhibitors of aspartic (pepstatin) or serine (PMSF, DFP) proteinases [24].

Physical interactions of ANK1

• The AE1 binding domain of ankyrin consists of 24 tandem repeats of a 33-amino acid motif that is present on a wide variety of otherwise unrelated proteins [17].
• Vaccinia virus K1L protein supports viral replication in human and rabbit cells through a cell-type-specific set of its ankyrin repeat residues that are distinct from its binding site for ACAP2 [3].
• The hydrophilic domain of small ankyrin-1 interacts with the two N-terminal immunoglobulin domains of titin [26].
• These studies have enabled us to identify a potentially important functional role for protein 4.1 in modulating ankyrin binding to CD44 [27].
• These findings suggest a general mechanism for the patterning of cell contact based on external signals that regulate tyrosine phosphorylation of L1CAM members and modulate their binding to ankyrin [5].

Enzymatic interactions of ANK1

• A preliminary estimate indicates that both human erythrocyte membrane and cytosolic casein kinase II catalyze the incorporation of approximately 1.2 and 3.5 moles of phosphate into each mole of spectrin and ankyrin, respectively [28].

Regulatory relationships of ANK1

• Nrarp (Notch-regulated ankyrin repeat protein) is a small protein that has two ankyrin repeats [29].
• Death-associated protein (DAP)-kinase is a calcium/calmodulin regulated serine/threonine kinase that carries ankyrin repeats, a death domain, and is localized to the cytoskeleton [30].
• Nuclear expression and consequent biological action of the eukaryotic NF-kappa B transcription factor complex are tightly regulated through its cytoplasmic retention by an ankyrin-rich inhibitory protein termed I kappa B alpha [31].
• Thus, Notch4-induced inhibition of sprouting requires the ankyrin repeats and appears to involve RBP-Jkappa-dependent and -independent signaling [32].
• However, a recent publication from the Felsenfeld laboratory () fills a gap in our knowledge of how the interaction of L1-type CAMs with the membrane skeleton adaptor protein ankyrin is severed by phosphorylation and suggests a feedback mechanism whereby the neurite-stimulating activity of L1-CAM is inversely connected to its cytoskeleton binding [33].

Other interactions of ANK1

• Human 220-kDa ankyrin-B, a closely related ankyrin isoform, is incapable of preserving the lateral membrane following 190-kDa ankyrin-G depletion [34].
• It also showed physical linkage of ANK1 and PLAT genes, which appear to be separated by a maximum of 700 kb [35].
• Association of the brain anion exchanger, AE3, with the repeat domain of ankyrin [22].
• Ankyrins from brain and erythrocytes have a similar domain structure with protease-resistant domains of Mr = 72,000 that contain spectrin-binding activity, and domains of Mr = 95,000 (brain ankyrin) or 90,000 (erythrocyte ankyrin) that contain binding sites for both tubulin and the anion channel [18].
• The oligonucleotide primer pairs for the microsatellite DNA markers were D8S133, D8S136, D8S137, ANK1 on chromosome 8p12-21, LPLTET on chromosome 8p22, and D17S855 (intragenic to the BRCA1 gene) on chromosome 17q21 [36].

Analytical, diagnostic and therapeutic context of ANK1

• Association was assessed by co-immunoprecipitation of ANK90-anion exchanger complexes from detergent extracts of cells cotransfected with plasmids encoding the ankyrin fragment and the anion exchanger or mutants thereof [22].
• In order to verify the efficiency of this screening we screened the ankyrin-1 gene of 22 Czech dHS patients for both the reduced cDNA allele expression in the frequent (AC)n and the common exonic 26/39 polymorphisms, as well as for polymerase chain reaction (PCR) single-stranded conformation polymorphisms in any one of the 42 exons of ANK1 [37].
• The present study reports the use of these antibodies to develop a radioimmunoassay capable of detecting femtomolar quantities of ankyrin, and demonstrates the presence of small but significant amounts of immunoreactivity in a variety of types of cells and tissues [38].
• Double labeling and confocal microscopy techniques show that NBD-lipids, band 3 protein, protein 4.1, ankyrin, and spectrin are all sequestered within sickle red cells and colocalized at sites of Heinz bodies [39].
• The phosphorylation state of the FIGQY tyrosine of neurofascin determines ankyrin-binding activity and patterns of cell segregation [5].

References