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214  structures 897  species 7  interactions 8812  sequences 2020  architectures

Family: Ank (PF00023)

Summary: Ankyrin repeat

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Ankyrin repeat Edit Wikipedia article

Ankyrin repeat domain
Ankyrin R membrane-binding domain 1N11.png
Ribbon diagram of a fragment of the membrane-binding domain of ankyrin R.[1]
Identifiers
Symbol Ank
Pfam PF00023
InterPro IPR002110
SMART SM00248
PROSITE PDOC50088
SCOP 1awc
SUPERFAMILY 1awc

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 repeats mediate protein-protein interactions and are among the most common structural motifs in known proteins. They appear in bacterial, archaeal, and eukaryotic proteins, but are far more common in eukaryotes. Ankyrin repeat proteins, though absent in most viruses, are common among poxviruses. Most proteins that contain the motif have four to six repeats, although its namesake ankyrin contains 24, and the largest known number of repeats is 34, predicted in a protein expressed by Giardia lamblia.[2]

Ankyrin repeats typically fold together to form a single, linear solenoid structure called ankyrin repeat domains. These domains are one of the most common protein–protein interaction platforms in nature. 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.[3] 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 that is universally recognised by it.

Role in protein folding[edit]

The ankyrin-repeat sequence motif has been studied using multiple sequence alignment to determine which conserved amino acid residues are critical for folding and stability. The residues that appear on the wide lateral surface of ankyrin repeat structures are variable, often hydrophobic, and involved mainly in mediating protein–protein interactions. An artificial protein design based on a consensus sequence derived from sequence alignment has been synthesized and found to fold stably, representing the first designed protein with multiple identical repeats.[4] More extensive design strategies have used combinatorial sequences to "evolve" ankyrin-repeat motifs that specifically recognize particular protein targets, a technique that has been presented as a possible alternative to antibody design for applications requiring high-affinity binding.[5]

Ankyrin-repeat proteins present an unusual problem in the study of protein folding, which has largely focused on globular proteins that form well-defined tertiary structure stabilized by long-range, nonlocal residue-residue contacts. Ankyrin repeats, by contrast, contain very few such contacts (that is, they have a low contact order). Most studies have found that ankyrin repeats fold in a two-state folding mechanism, suggesting a high degree of folding cooperativity despite the local inter-residue contacts and the evident need for successful folding with varying numbers of repeats. Some evidence, based on synthesis of truncated versions of natural repeat proteins,[6] and on the examination of phi values,[7] suggests that the C-terminus forms the folding nucleation site.

Clinical significance[edit]

Ankyrin-repeat proteins have been associated with a number of human diseases. These proteins include the cell cycle inhibitor p16, which is associated with cancer, and the Notch protein (a key component of cell signalling pathways) which can cause the neurological disorder CADASIL when the repeat domain is disrupted by mutations.[2]

A specialized family of ankyrin proteins known as muscle ankyrin repeat proteins (MARPs) are involved with the repair and regeneration of muscle tissue following damage due to injury and stress.[8]

A natural variation between glutamine and lysine at position 703 in the 11th ankyrin repeat of ANKK1, known as the TaqI A1 allele,[9] has been credited with encouraging addictive behaviours such as obesity, alcoholism, nicotine dependency and the Eros love style[citation needed] while discouraging juvenile delinquency and neuroticism-anxiety.[10][not in citation given] The variation may affect the specificity of protein interactions made by the ANKK1 protein kinase through this repeat[citation needed].

Human proteins containing this repeat[edit]

ABTB1; ABTB2; ACBD6; ACTBL1; ANK1; ANK2; ANK3; ANKAR; ANKDD1A; ANKEF1; ANKFY1; ANKHD1; ANKIB1; ANKK1; ANKMY1; ANKMY2; ANKRA2; ANKRD1; ANKRD10; ANKRD11; ANKRD12; ANKRD13; ANKRD13A; ANKRD13B; ANKRD13C; ANKRD13D; ANKRD15; ANKRD16; ANKRD17; ANKRD18A; ANKRD18B; ANKRD19; ANKRD2; ANKRD20A1; ANKRD20A2; ANKRD20A3; ANKRD20A4; ANKRD21; ANKRD22; ANKRD23; ANKRD25; ANKRD26; ANKRD27; ANKRD28; ANKRD30A; ANKRD30B; ANKRD30BL; ANKRD32; ANKRD33; ANKRD35; ANKRD36; ANKRD36B; ANKRD37; ANKRD38; ANKRD39; ANKRD40; ANKRD41; ANKRD42; ANKRD43; ANKRD44; ANKRD45; ANKRD46; ANKRD47; ANKRD49; ANKRD50; ANKRD52; ANKRD53; ANKRD54; ANKRD55; ANKRD56; ANKRD57; ANKRD58; ANKRD60; ANKRD6; ANKRD7; ANKRD9; ANKS1A; ANKS3; ANKS4B; ANKS6; ANKZF1; ASB1; ASB10; ASB11; ASB12; ASB13; ASB14; ASB15; ASB16; ASB2; ASB3; ASB4; ASB5; ASB6; ASB7; ASB8; ASB9; ASZ1; BARD1; BAT4; BAT8; BCL3; BCOR; BCORL1; BTBD11; CAMTA1; CAMTA2; CASKIN1; CASKIN2; CCM1; CDKN2A; CDKN2B; CDKN2C; CDKN2D; CENTB1; CENTB2; CENTB5; CENTG1; CENTG2; CENTG3; CLIP3; CLIP4; CLPB; CTGLF1; CTGLF2; CTGLF3; CTGLF4; CTGLF5; CTTNBP2; DAPK1; DDEF1; DDEF2; DDEFL1; DGKI; DGKZ; DP58; DYSFIP1; DZANK; EHMT1; EHMT2; ESPN; FANK1; FEM1A; FEM1B; GABPB2; GIT1; GIT2; GLS; GLS2; HACE1; HECTD1; IBTK; ILK; INVS; KIDINS220; KRIT1; LRRK1; MAIL; MIB1; MIB2; MPHOSPH8; MTPN; MYO16; NFKB1; NFKB2; NFKBIA; NFKBIB; NFKBIE; NFKBIL1; NFKBIL2; NOTCH1; NOTCH2; NOTCH3; NOTCH4; NRARP; NUDT12; OSBPL1A; OSTF1; PLA2G6; POTE14; POTE15; POTE8; PPP1R12A; PPP1R12B; PPP1R12C; PPP1R13B; PPP1R13L; PPP1R16A; PPP1R16B; PSMD10; RAI14; RFXANK; RIPK4; RNASEL; SHANK1; SHANK2; SHANK3; SNCAIP; TA-NFKBH; TEX14; TNKS; TNKS2; TNNI3K; TP53BP2; TRP7; TRPA1; TRPC3; TRPC4; TRPC5; TRPC6; TRPC7; TRPV1; TRPV2; TRPV3; TRPV4; TRPV5; TRPV6; UACA; USH1G; ZDHHC13; ZDHHC17;

See also[edit]

  • DARPin (designed ankyrin repeat protein), an engineered antibody mimetic based on the structure of ankyrin repeats

References[edit]

  1. ^ PDB 1N11; Michaely P, Tomchick DR, Machius M, Anderson RG (December 2002). "Crystal structure of a 12 ANK repeat stack from human ANK1". EMBO J. 21 (23): 6387–96. doi:10.1093/emboj/cdf651. PMC 136955. PMID 12456646. 
  2. ^ a b Mosavi L, Cammett T, Desrosiers D, Peng Z (2004). "The ankyrin repeat as molecular architecture for protein recognition". Protein Sci 13 (6): 1435–48. doi:10.1110/ps.03554604. PMC 2279977. PMID 15152081. 
  3. ^ Bork P (December 1993). "Hundreds of ankyrin-like repeats in functionally diverse proteins: mobile modules that cross phyla horizontally?". Proteins 17 (4): 363–74. doi:10.1002/prot.340170405. PMID 8108379. 
  4. ^ Mosavi LK, Minor DL, Peng ZY (Dec 2002). "Consensus-derived structural determinants of the ankyrin repeat motif". Proc Natl Acad Sci USA. 99 (25): 16029–34. Bibcode:2002PNAS...9916029M. doi:10.1073/pnas.252537899. PMC 138559. PMID 12461176. 
  5. ^ Binz HK, Amstutz P, Kohl A, et al. (May 2004). "High-affinity binders selected from designed ankyrin repeat protein libraries". Nat Biotechnol. 22 (5): 575–82. doi:10.1038/nbt962. PMID 15097997. 
  6. ^ Zhang B, Peng Z (Jun 2000). "A minimum folding unit in the ankyrin repeat protein p16(INK4)". J Mol Biol. 299 (4): 1121–32. doi:10.1006/jmbi.2000.3803. PMID 10843863. 
  7. ^ Tang KS, Fersht AR, Itzhaki LS (Jan 2003). "Sequential unfolding of ankyrin repeats in tumor suppressor p16". Structure 11 (1): 67–73. doi:10.1016/S0969-2126(02)00929-2. PMID 12517341. 
  8. ^ Miller MK, Bang ML, Witt CC, et al. (Nov 2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". J Mol Biol. 333 (5): 951–64. doi:10.1016/j.jmb.2003.09.012. PMID 14583192. 
  9. ^ Neville MJ, Johnstone EC, Walton RT (Jun 2004). "Identification and characterization of ANKK1: a novel kinase gene closely linked to DRD2 on chromosome band 11q23.1". Hum Mutat. 23 (6): 540–5. doi:10.1002/humu.20039. PMID 15146457. 
  10. ^ "NCBI Gene summary for DRD2".  (interim reference)

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR002110

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Ankyrin repeat Provide feedback

Ankyrins are multifunctional adaptors that link specific proteins to the membrane-associated, spectrin- actin cytoskeleton. This repeat-domain is a 'membrane-binding' domain of up to 24 repeated units, and it mediates most of the protein's binding activities. Repeats 13-24 are especially active, with known sites of interaction for the Na/K ATPase, Cl/HCO(3) anion exchanger, voltage-gated sodium channel, clathrin heavy chain and L1 family cell adhesion molecules. The ANK repeats are found to form a contiguous spiral stack such that ion transporters like the anion exchanger associate in a large central cavity formed by the ANK repeat spiral, while clathrin and cell adhesion molecules associate with specific regions outside this cavity [2].

Literature references

  1. Lux SE, John KM, Bennett V; , Nature 1990;345:736-739.: Hereditary spherocytosis associated with deletion of human erythrocyte ankyrin gene on chromosome 8. PUBMED:2141669 EPMC:2141669

  2. Michaely P, Tomchick DR, Machius M, Anderson RG;, EMBO J. 2002;21:6387-6396.: Crystal structure of a 12 ANK repeat stack from human ankyrinR. PUBMED:12456646 EPMC:12456646

  3. Michaely P, Bennett V;, Trends Cell Biol. 1992;2:127-129.: The ANK repeat: a ubiquitous motif involved in macromolecular recognition. PUBMED:14731966 EPMC:14731966


External database links

This tab holds annotation information from the InterPro database.

InterPro entry 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].

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Ank (CL0465), which has the following description:

The ankyrin repeat is a short sequence region that is about 30-34 amino-acids in length. Multiple copies of the repeat composed of two beta strands and two alpha helices combine to form long arrays. In general these repeats are involved in protein-protein interactions. This superfamily also includes some families that are arrays of several repeats.

The clan contains the following 7 members:

Ank Ank_2 Ank_3 Ank_4 Ank_5 DUF3420 DUF3447

Alignments

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(1072)
Full
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Representative proteomes NCBI
(139773)
Meta
(9187)
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(2564)
RP35
(3256)
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  Seed
(1072)
Full
(8812)
Representative proteomes NCBI
(139773)
Meta
(9187)
RP15
(2564)
RP35
(3256)
RP55
(4303)
RP75
(5230)
Alignment:
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  Seed
(1072)
Full
(8812)
Representative proteomes NCBI
(139773)
Meta
(9187)
RP15
(2564)
RP35
(3256)
RP55
(4303)
RP75
(5230)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Swissprot_feature_table
Previous IDs: ank;
Type: Repeat
Author: Bateman A, Sonnhammer ELL
Number in seed: 1072
Number in full: 8812
Average length of the domain: 32.40 aa
Average identity of full alignment: 29 %
Average coverage of the sequence by the domain: 5.11 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 14.7
Trusted cut-off 20.6 14.7
Noise cut-off 20.5 14.6
Model length: 33
Family (HMM) version: 25
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Species distribution

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Interactions

There are 7 interactions for this family. More...

RHD Ank SH3_1 Pkinase P53 ArfGap TIG

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ank domain has been found. There are 214 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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