Summary: Ankyrin repeat
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Ankyrin repeat Edit Wikipedia article
|Ankyrin repeat domain|
|Ribbon diagram of a fragment of the membrane-binding domain of ankyrin R.|
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.
 Clinical significance
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; 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; ANKRD32; ANKRD33; ANKRD35; ANKRD36; ANKRD36B; ANKRD37; ANKRD38; ANKRD39; ANKRD40; ANKRD41; ANKRD42; ANKRD43; ANKRD44; ANKRD45; ANKRD46; ANKRD47; ANKRD49; ANKRD5; ANKRD50; ANKRD52; ANKRD53; ANKRD54; ANKRD55; ANKRD56; ANKRD57; ANKRD58; 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; C20orf12; C20orf86; C21orf99; C7orf7; 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; EHMT1; EHMT2; ESPN; FANK1; FEM1A; FEM1B; GABPB2; GIT1; GIT2; GLS; GLS2; HACE1; HECTD1; IBTK; ILK; INVS; KIDINS220; KRIT1; LOC348840; LOC554226; LRRK1; MAIL; MGC26718; MGC29891; 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
- 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. //www.ncbi.nlm.nih.gov/pmc/articles/PMC136955/.
- 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. http://www.proteinscience.org/cgi/content/full/13/6/1435.
- 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. http://www.pnas.org/cgi/content/full/99/25/16029.
- 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. http://linkinghub.elsevier.com/retrieve/pii/S0969212602009292.
- 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. http://linkinghub.elsevier.com/retrieve/pii/S0022283603011380.
- 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". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1813&ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum. (interim reference)
- Eukaryotic Linear Motif resource motif class LIG_TNKBM
- Ankyrin repeat at the US National Library of Medicine Medical Subject Headings (MeSH)
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 .
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].
|Molecular function||protein binding (GO:0005515)|
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|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 %|
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build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||25|
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There are 7 interactions for this family. More...
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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