Summary: Ankyrin repeats (3 copies)
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Ankyrin repeat Edit Wikipedia article
|Ankyrin repeat domain|
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.
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. 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
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. 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.
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, and on the examination of phi values, suggests that the C-terminus forms the folding nucleation site.
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.
A natural variation between glutamine and lysine at position 703 in the 11th ankyrin repeat of ANKK1, known as the TaqI A1 allele, has been credited with encouraging addictive behaviours such as obesity, alcoholism, nicotine dependency and the Eros love style while discouraging juvenile delinquency and neuroticism-anxiety.[not in citation given] The variation may affect the specificity of protein interactions made by the ANKK1 protein kinase through this repeat.
Human proteins containing this repeat
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;
- DARPin (designed ankyrin repeat protein), an engineered antibody mimetic based on the structure of ankyrin repeats
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- "NCBI Gene summary for DRD2". (interim reference)
- Eukaryotic Linear Motif resource motif class LIG_TNKBM_1
- Ankyrin repeat at the US National Library of Medicine Medical Subject Headings (MeSH)
Ankyrin repeats (3 copies) Provide feedback
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Internal database links
|Similarity to PfamA using HHSearch:||Ank Ank Shigella_OspC Shigella_OspC DUF3447 DUF3447 Ank_3 Ank_3 Ank_4 Ank_4 Ank_5 Ank_5|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR020683
This entry represents the ankyrin repeat-containing domain. These domains contain multiple repeats of a beta(2)-alpha(2) motif. 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].
- the number of sequences which exhibit this architecture
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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
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Curation and family details
|Number in seed:||620|
|Number in full:||110723|
|Average length of the domain:||89.50 aa|
|Average identity of full alignment:||23 %|
|Average coverage of the sequence by the domain:||36.39 %|
|HMM build commands:||
build method: hmmbuild --amino -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||2|
|Download:||download the raw HMM for this family|
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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_2 domain has been found. There are 200 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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