The domain within your query sequence starts at position 708 and ends at position 737; the E-value for the ANK domain shown below is 3.95e1.

LKNTMLERACDQNNSIMVECLLLLGADANQ

ANK

ankyrin repeats

• 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 90^o angle. The repeats stack together to form an L-shaped structure [(PUBMED:8875926), (PUBMED:12461176)].

• GO function: protein binding (GO:0005515)

There are 146742 ANK domains in 25863 proteins in SMART's nrdb database.

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

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

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

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

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

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 OMIM:209920:
Ankyrin-1 (P16157) (SMART)	OMIM:182900: Spherocytosis-2

Metabolism (metabolic pathways involving proteins which contain this domain)

% 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	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