|SMART accession number:||SM00248|
|Description:||Ankyrin repeats are about 33 amino acids long and occur in at least four consecutive copies. They are involved in protein-protein interactions. The core of the repeat seems to be an helix-loop-helix structure.|
|Interpro abstract (IPR002110):|
The ankyrin repeat is one of the most common protein-protein interaction motifs in nature. Ankyrin repeats are tandemly repeated modules of about 33 amino acids. They occur in a large number of functionally diverse proteins mainly from eukaryotes. The few known examples from prokaryotes and viruses may be the result of horizontal gene transfers [(PUBMED:8108379)]. The repeat has been found in proteins of diverse function such as transcriptional initiators, cell-cycle regulators, cytoskeletal, ion transporters and signal transducers. The ankyrin fold appears to be defined by its structure rather than its function since there is no specific sequence or structure which is universally recognised by it.
The conserved fold of the ankyrin repeat unit is known from several crystal and solution structures [(PUBMED:8875926), (PUBMED:9353127), (PUBMED:9461436), (PUBMED:9865693)]. Each repeat folds into a helix-loop-helix structure with a beta-hairpin/loop region projecting out from the helices at a 90o angle. The repeats stack together to form an L-shaped structure [(PUBMED:8875926), (PUBMED:12461176)].
|GO function:||protein binding (GO:0005515)|
Click on the following links for more information.
- Evolution (species in which this domain is found)
Click on to expand nodes. To display all proteins with a ANK domain in a specific node, click on it.
This tree shows only several representative species. The complete taxonomic breakdown of all proteins with ANK domain is also avaliable.
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Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes
- Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Mandiyan V, Andreev J, Schlessinger J, Hubbard SR
- Crystal structure of the ARF-GAP domain and ankyrin repeats of PYK2-associated protein beta.
- EMBO J. 1999; 18: 6890-8
- Display abstract
ADP ribosylation factors (ARFs), which are members of the Ras superfamily of GTP-binding proteins, are critical components of vesicular trafficking pathways in eukaryotes. Like Ras, ARFs are active in their GTP-bound form, and their duration of activity is controlled by GTPase-activating proteins (GAPs), which assist ARFs in hydrolyzing GTP to GDP. PAPbeta, a protein that binds to and is phosphorylated by the non-receptor tyrosine kinase PYK2, contains several modular signaling domains including a pleckstrin homology domain, an SH3 domain, ankyrin repeats and an ARF-GAP domain. Sequences of ARF-GAP domains show no recognizable similarity to those of other GAPs, and contain a characteristic Cys-X(2)-Cys-X(16-17)-Cys-X(2)-Cys motif. The crystal structure of the PAPbeta ARF-GAP domain and the C-terminal ankyrin repeats has been determined at 2.1 A resolution. The ARF-GAP domain comprises a central three-stranded beta-sheet flanked by five alpha-helices, with a Zn(2+) ion coordinated by the four cysteines of the cysteine-rich motif. Four ankyrin repeats are also present, the first two of which form an extensive interface with the ARF-GAP domain. An invariant arginine and several nearby hydrophobic residues are solvent exposed and are predicted to be the site of interaction with ARFs. Site-directed mutagenesis of these residues confirms their importance in ARF-GAP activity.
- Jacobs MD, Harrison SC
- Structure of an IkappaBalpha/NF-kappaB complex.
- Cell. 1998; 95: 749-58
- Display abstract
The inhibitory protein, IkappaBalpha, sequesters the transcription factor, NF-kappaB, as an inactive complex in the cytoplasm. The structure of the IkappaBalpha ankyrin repeat domain, bound to a partially truncated NF-kappaB heterodimer (p50/ p65), has been determined by X-ray crystallography at 2.7 A resolution. It shows a stack of six IkappaBalpha ankyrin repeats facing the C-terminal domains of the NF-kappaB Rel homology regions. Contacts occur in discontinuous patches, suggesting a combinatorial quality for ankyrin repeat specificity. The first two repeats cover an alpha helically ordered segment containing the p65 nuclear localization signal. The position of the sixth ankyrin repeat shows that full-length IkappaBalpha will occlude the NF-kappaB DNA-binding cleft. The orientation of IkappaBalpha in the complex places its N- and C-terminal regions in appropriate locations for their known regulatory functions.
- Bork P
- Hundreds of ankyrin-like repeats in functionally diverse proteins: mobile modules that cross phyla horizontally?
- Proteins. 1993; 17: 363-74
- Display abstract
Based on pattern searches and systematic database screening, almost 650 different ankyrin-like (ANK) repeats from nearly all phyla have been identified; more than 150 of them are reported here for the first time. Their presence in functionally diverse proteins such as enzymes, toxins, and transcription factors strongly suggests domain shuffling, but their occurrence in prokaryotes and yeast excludes exon shuffling. The spreading mechanism remains unknown, but in at least three cases horizontal gene transfer appears to be involved. ANK repeats occur in at least four consecutive copies. The terminal repeats are more variable in sequence. One feature of the internal repeats is a predicted central hydrophobic alpha-helix, which is likely to interact with other repeats. The functions of the ankyrin-like repeats are compatible with a role in protein-protein interactions.
- Davis LH, Otto E, Bennett V
- Specific 33-residue repeat(s) of erythrocyte ankyrin associate with the anion exchanger.
- J Biol Chem. 1991; 266: 11163-9
- Display abstract
Erythrocyte ankyrin contains an 89-kDa domain (residues 2-827) comprised almost entirely of 22 tandem repeats of 33 amino acids which are responsible for the high affinity interaction of ankyrin with the anion exchanger (Davis, L., and Bennett, V. (1990) J. Biol. Chem. 265, 10589-10596). The question of whether the repeats are equivalent with respect to binding to the anion exchanger was addressed using defined regions of erythrocyte and brain ankyrins expressed in bacteria. The conclusion is that the repeats are not interchangeable and that the 44 residues from 722 to 765 are essential for high affinity binding between erythrocyte ankyrin and the anion exchanger. Residues 348-765 were active whereas a polypeptide of the same size (residues 305-721) but missing the 44 residues was not active. The difference between the active and inactive polypeptides was not caused by the degree of folding based on circular dichroism spectra. The 44 residues from 722 to 765 were not sufficient for binding since deletions of residues from 348 to 568 resulted in a 10-fold loss of activity. However, the role of residues 348-568 may be at the level of folding rather than a direct contact since the deleted sequences were not active in the absence of 722-765 and since circular dichroism spectra revealed significant loss of structure in the smaller polypeptides. Further evidence that the 33-residue repeats are not equivalent in ability to bind to the anion exchanger is that a region of human brain ankyrin containing 18 33-residue repeats with 67% overall sequence identity to erythrocyte ankyrin was 8-fold less active than a region of erythrocyte ankyrin containing only 12 repeats. The fact that the anion exchanger binds to certain repeats suggests that the other 33-amino acid repeats could interact with proteins distinct from the anion exchanger and provide ankyrin with the potential for considerable diversity in association with membrane proteins as well as cytoplasmic proteins. Tubulin was identified as one example of a protein that can interact with ankyrin repeats that are not recognized by the anion exchanger.
- Lux SE, John KM, Bennett V
- Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue-differentiation and cell-cycle control proteins.
- Nature. 1990; 344: 36-42
- Display abstract
Analysis of complementary DNA for human erythroid ankyrin indicates that the mature protein contains 1,880 amino acids comprising an N-terminal domain binding integral membrane proteins and tubulin, a central domain binding spectrin and vimentin, and an acidic C-terminal 'regulatory' domain containing an alternatively spliced sequence missing from ankyrin variant 2.2. The N-terminal domain is almost entirely composed of 22 tandem 33-amino-acid repeats. Similar repeats are found in yeast and invertebrate proteins involved in cell-cycle control and tissue differentiation.
- Disease (disease genes where sequence variants are found in this domain)
SwissProt sequences and OMIM curated human diseases associated with missense mutations within the ANK domain.
Protein Disease DNA-binding protein RFXANK (O14593) (SMART) OMIM:603200: MHC class II deficiency, complementation group B
Ankyrin-1 (P16157) (SMART) OMIM:182900: Spherocytosis-2
- Metabolism (metabolic pathways involving proteins which contain this domain)
Click the image to view the interactive version of the map in iPath
% proteins involved KEGG pathway ID Description 5.56 map04662 B cell receptor signaling pathway 5.56 map04660 T cell receptor signaling pathway 5.56 map04920 Adipocytokine signaling pathway 4.42 map05120 Epithelial cell signaling in Helicobacter pylori infection 3.99 map05222 Small cell lung cancer 3.85 map04320 Dorso-ventral axis formation 3.85 map04330 Notch signaling pathway 3.71 map05220 Chronic myeloid leukemia 3.57 map04210 Apoptosis 3.57 map04620 Toll-like receptor signaling pathway 3.57 map05215 Prostate cancer 2.85 map04010 MAPK signaling pathway 2.57 map00910 Nitrogen metabolism 2.43 map00564 Glycerophospholipid metabolism 2.28 map05212 Pancreatic cancer 2.28 map04510 Focal adhesion 2.14 map00471 D-Glutamine and D-glutamate metabolism 2.14 map05221 Acute myeloid leukemia 2.14 map00251 Glutamate metabolism 2.14 map04810 Regulation of actin cytoskeleton 2.00 map04111 Cell cycle - yeast 1.85 map04110 Cell cycle 1.85 map03050 Proteasome 1.57 map04070 Phosphatidylinositol signaling system 1.57 map05219 Bladder cancer 1.43 map00561 Glycerolipid metabolism 1.43 map00310 Lysine degradation 1.14 map05213 Endometrial cancer 1.14 map04720 Long-term potentiation 1.14 map00380 Tryptophan metabolism 1.14 map03320 PPAR signaling pathway 1.00 map04612 Antigen processing and presentation 1.00 map05020 Parkinson's disease 0.86 map00760 Nicotinate and nicotinamide metabolism 0.86 map04080 Neuroactive ligand-receptor interaction 0.71 map04664 Fc epsilon RI signaling pathway 0.71 map04730 Long-term depression 0.71 map04370 VEGF signaling pathway 0.71 map00590 Arachidonic acid metabolism 0.71 map00565 Ether lipid metabolism 0.71 map04912 GnRH signaling pathway 0.71 map00592 alpha-Linolenic acid metabolism 0.71 map00591 Linoleic acid metabolism 0.43 map00350 Tyrosine metabolism 0.43 map04350 TGF-beta signaling pathway 0.43 map00460 Cyanoamino acid metabolism 0.43 map00632 Benzoate degradation via CoA ligation 0.43 map00252 Alanine and aspartate metabolism 0.43 map00340 Histidine metabolism 0.43 map00562 Inositol phosphate metabolism 0.29 map00150 Androgen and estrogen metabolism 0.29 map00626 Naphthalene and anthracene degradation 0.29 map00051 Fructose and mannose metabolism 0.29 map00440 Aminophosphonate metabolism 0.29 map00450 Selenoamino acid metabolism 0.14 map00642 Ethylbenzene degradation 0.14 map05214 Glioma 0.14 map04115 p53 signaling pathway 0.14 map00360 Phenylalanine metabolism 0.14 map00790 Folate biosynthesis 0.14 map03060 Protein export 0.14 map05223 Non-small cell lung cancer 0.14 map00903 Limonene and pinene degradation 0.14 map00960 Alkaloid biosynthesis II 0.14 map00624 1- and 2-Methylnaphthalene degradation 0.14 map00230 Purine metabolism 0.14 map05218 Melanoma
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ANK domain which could be assigned to a KEGG orthologous group, and not all proteins containing ANK domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
- Structure (3D structures containing this domain)
3D Structures of ANK domains in PDB
PDB code Main view Title 1a5e Solution nmr structure of tumor suppressor p16ink4a, 18 structures 1ap7 P19-ink4d from mouse, nmr, 20 structures 1awc Mouse gabp alpha/beta domain bound to dna 1bd8 Structure of cdk inhibitor p19ink4d 1bi7 Mechanism of g1 cyclin dependent kinase inhibition from the structure of the cdk6-p16ink4a tumor suppressor complex 1bi8 Mechanism of g1 cyclin dependent kinase inhibition from the structures cdk6-p19ink4d inhibitor complex 1blx P19ink4d/cdk6 complex 1bu9 Solution structure of p18-ink4c, 21 structures 1d9s Tumor suppressor p15(ink4b) structure by comparative modeling and nmr data 1dc2 Solution nmr structure of tumor suppressor p16ink4a, 20 structures 1dcq Crystal structure of the arf-gap domain and ankyrin repeats of papbeta. 1g3n Structure of a p18(ink4c)-cdk6-k-cyclin ternary complex 1ihb Crystal structure of p18-ink4c(ink6) 1ikn Ikappabalpha/nf-kappab complex 1ixv Crystal structure analysis of homolog of oncoprotein gankyrin, an interactor of rb and cdk4/6 1k1a Crystal structure of the ankyrin repeat domain of bcl-3: a unique member of the ikappab protein family 1k1b Crystal structure of the ankyrin repeat domain of bcl-3: a unique member of the ikappab protein family 1k3z X-ray crystal structure of the ikbb/nf-kb p65 homodimer complex 1mj0 Sank e3_5: an artificial ankyrin repeat protein 1mx2 Structure of f71n mutant of p18ink4c 1mx4 Structure of p18ink4c (f82q) 1mx6 Structure of p18ink4c (f92n) 1myo Solution structure of myotrophin, nmr, 44 structures 1n0q 3ank: a designed ankyrin repeat protein with three identical consensus repeats 1n0r 4ank: a designed ankyrin repeat protein with four identical consensus repeats 1n11 D34 region of human ankyrin-r and linker 1nfi I-kappa-b-alpha/nf-kappa-b complex 1ot8 Structure of the ankyrin domain of the drosophila notch receptor 1oy3 Crystal structure of an ikbbeta/nf-kb p65 homodimer complex 1qym X-ray structure of human gankyrin 1s70 Complex between protein ser/thr phosphatase-1 (delta) and the myosin phosphatase targeting subunit 1 (mypt1) 1svx Crystal structure of a designed selected ankyrin repeat protein in complex with the maltose binding protein 1sw6 S. cerevisiae swi6 ankyrin-repeat fragment 1tr4 Solution structure of human oncogenic protein gankyrin 1uoh Human gankyrin 1wdy Crystal structure of ribonuclease 1wg0 Structural comparison of nas6p protein structures in two different crystal forms 1ycs P53-53bp2 complex 1ymp The crystal structure of a partial mouse notch-1 ankyrin domain: repeats 4 through 7 preserve an ankyrin fold 1yyh Crystal structure of the human notch 1 ankyrin domain 2a5e Solution nmr structure of tumor suppressor p16ink4a, restrained minimized mean structure 2aja X-ray structure of an ankyrin repeat family protein q5zsv0 from legionella pneumophila. northeast structural genomics consortium target lgr21. 2b0o Crystal structure of uplc1 gap domain 2bkg Crystal structure of e3_19 an designed ankyrin repeat protein 2bkk Crystal structure of aminoglycoside phosphotransferase aph (3')-iiia in complex with the inhibitor ar_3a 2di3 Crystal structure of the transcriptional factor cgl2915 from corynebacterium glutamicum 2dvw Structure of the oncoprotein gankyrin in complex with s6 atpase of the 26s proteasome 2dwz Structure of the oncoprotein gankyrin in complex with s6 atpase of the 26s proteasome 2dzn Crystal structure analysis of yeast nas6p complexed with the proteasome subunit, rpt3 2dzo Crystal structure analysis of yeast nas6p complexed with the proteasome subunit, rpt3 2eta Crystal structure of the ankyrin repeat domain of the trpv2 2etb Crystal structure of the ankyrin repeat domain of trpv2 2etc Crystal structure of the ankyrin repeat domain of trpv2 2f37 Crystal structure of the ankyrin repeat domain of human trpv2 2f8x Crystal structure of activated notch, csl and maml on hes-1 promoter dna sequence 2f8y Crystal structure of human notch1 ankyrin repeats to 1.55a resolution. 2fo1 Crystal structure of the csl-notch-mastermind ternary complex bound to dna 2he0 Crystal structure of a human notch1 ankyrin domain mutant 2j8s Drug export pathway of multidrug exporter acrb revealed by darpin inhibitors 2jab A designed ankyrin repeat protein evolved to picomolar affinity to her2 2kbx Solution structure of ilk-pinch complex 2myo Solution structure of myotrophin, nmr, minimized average structure 2nyj Crystal structure of the ankyrin repeat domain of trpv1 2p2c Inhibition of caspase-2 by a designed ankyrin repeat protein (darpin) 2pnn Crystal structure of the ankyrin repeat domain of trpv1 2qc9 Mouse notch 1 ankyrin repeat intracellular domain 2qyj Crystal structure of a designed full consensus ankyrin 2rfa Crystal structure of the mouse trpv6 ankyrin repeat domain 2rfm Structure of a thermophilic ankyrin repeat protein 2v4h Nemo cc2-lz domain - 1d5 darpin complex 2v5q Crystal structure of wild-type plk-1 kinase domain in complex with a selective darpin 2vge Crystal structure of the c-terminal region of human iaspp 2zgd Asn-hydroxylation stabilises the ankyrin repeat domain fold 2zgg Asn-hydroxylation stabilises the ankyrin repeat domain fold 3b7b Euhmt1 (glp) ankyrin repeat domain (structure 1) 3b95 Euhmt1 (glp) ankyrin repeat domain (structure 2) 3c5r Crystal structure of the bard1 ankyrin repeat domain and its functional consequences 3d9h Crystal structure of the splice variant of human asb9 (hasb9-2), an ankyrin repeat protein 3deo Structural basis for specific substrate recognition by the chloroplast signal recognition particle protein cpsrp43 3dep Structural basis for specific substrate recognition by the chloroplast signal recognition particle protein cpsrp43 3ehq Crystal structure of human osteoclast stimulating factor 3ehr Crystal structure of human osteoclast stimulating factor 3eu9 The ankyrin repeat domain of huntingtin interacting protein 3f6q Crystal structure of integrin-linked kinase ankyrin repeat domain in complex with pinch1 lim1 domain 3hg0 Crystal structure of a darpin in complex with orf49 from lactococcal phage tp901-1
- Links (links to other resources describing this domain)
PFAM ank INTERPRO IPR002110