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| Ankyrin repeat domain | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
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| Identifiers | |||||||||||
| Symbol | Ank | ||||||||||
| Pfam | PF00023 | ||||||||||
| InterPro | IPR002110 | ||||||||||
| SMART | SM00248 | ||||||||||
| PROSITE | PDOC50088 | ||||||||||
| SCOP2 | 1awc /SCOPe /SUPFAM | ||||||||||
| |||||||||||
Theankyrin repeat is a 33-residuemotif inproteins consisting of twoalpha helices separated byloops, first discovered insignaling proteins inyeast Cdc10 andDrosophilaNotch. Domains consisting of ankyrintandem repeats mediateprotein–protein interactions and are among the most common structural motifs in known proteins. They appear inbacterial,archaeal, andeukaryotic proteins, but are far more common in eukaryotes. Ankyrin repeat proteins, though absent in most viruses, are common amongpoxviruses. Most proteins that contain the motif have four to six repeats, although its namesakeankyrin contains 24, and the largest known number of repeats is 34, predicted in a protein expressed byGiardia lamblia.[2]
Ankyrin repeats typicallyfold together to form a single, linearsolenoid structure calledankyrin 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 fromeukaryotes. The few known examples fromprokaryotes 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, andsignal 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.
Considering the atomic structures of individual ankyrin repeats, the loop is often a type 1beta bulge loop, while both alpha-helices commonly have aSchellman loop at theirN-terminus.
The ankyrin-repeat sequence motif has been studied usingmultiple sequence alignment to determineconservedamino acid residues critical for folding and stability. The residues on the wide lateral surface of ankyrin repeat structures are variable, oftenhydrophobic, and involved mainly in mediating protein–protein interactions. An artificialprotein design based on aconsensus sequence derived from sequence alignment has been synthesized and found tofold stably, representing the first designed protein with multiple repeats.[4] More extensive design strategies have used combinatorial sequences to "evolve" ankyrin-repeats that recognize particular protein targets, a technique that has been presented as an alternative toantibody design for applications requiring high-affinity binding.[5] A structure-based study involving a range of ankyrin proteins of known structures, shows that consensus-based ankyrin proteins are very stable since they maximize the energetic gap between the folding and unfolding structures, encoding a densely connected network of favourable interactions among conserved sequence motifs, like the TPLX motif.[6] The same study shows that insertions in the canonical framework of ankyrin repeats are enriched in conflictive interactions, that are related to function. The same applies to interactions surrounding deletion hotspots. These might be related to complex folding/unfolding transitions that are important to the partner recognition and interaction.
Ankyrin-repeat proteins present an unusual problem in the study ofprotein folding, which has largely focused onglobular proteins that form well-definedtertiary structure stabilized by long-range, nonlocalresidue-residue contacts. Ankyrin repeats, by contrast, contain very few such contacts (that is, they have a lowcontact order). Most studies have found that ankyrin repeats fold in atwo-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,[7] and on the examination ofphi values,[8] suggests that theC-terminus forms the folding nucleation site.
Ankyrin-repeat proteins have been associated with a number of humandiseases. These proteins include thecell cycle inhibitorp16, which is associated withcancer, and the Notch protein (a key component of cell signalling pathways) which can cause the neurological disorderCADASIL 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 ofmuscle tissue following damage due to injury and stress.[9]
A natural variation betweenglutamine andlysine at position 703 in the 11th ankyrin repeat ofANKK1, known as the TaqI A1 allele,[10] has been credited with encouraging addictive behaviours such as obesity, alcoholism, nicotine dependency and the Eroslove style[citation needed] while discouraging juvenile delinquency and neuroticism-anxiety.[11][failed verification] The variation may affect the specificity of protein interactions made by the ANKK1 protein kinase through this repeat[citation needed].
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;ANKRD24;ANKRD25;ANKRD26;ANKRD27;ANKRD28;ANKRD30A;ANKRD30B;ANKRD30BL;ANKRD32;ANKRD33;ANKRD35;ANKRD36;ANKRD36B;ANKRD37;ANKRD38;ANKRD39;ANKRD40;ANKRD41;ANKRD42;ANKRD43;ANKRD44;ANKRD45;ANKRD46;ANKRD47;ANKRD49 [uk];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;