The Eukaryote Linear Motif resource for Functional Sites in Proteins
Accession:
Functional site class:
Tankyrase-binding motif
Functional site description:
Tankyrases belong to the poly (ADP-ribose) polymerase (PARP) family of proteins, which function by catalyzing the covalent linkage of ADP-ribose polymers onto target proteins and thereby regulating their ubiquitylation, stability and function. The human genome encodes two similar tankyrases. TNKS and TNKS2 both recruit a variety of substrates with a broad range of functions. Each shows some variation in their conservation and tissue expression. Moreover both Tankyrases contain N-terminal ankyrin repeats. These ankyrin repeats form five domains known as ankyrin repeat clusters (ARCs) and each can serve as a discrete binding site for its binding partners. Tankyrase plays important roles in many biological functions including telomere length regulation, insulin signalling and centrosome function. Dysregulation of 3BP2 recognition by tankyrase causes a human disease knows as cherubism. Tankyrase is also considered to be a potential candidate for a telomere-directed anticancer target.
ELM Description:
Tankyrase1 and Tankyrase 2 are closely related poly (ADP-ribose) polymerases. They have both enzymatic and scaffolding activities. Tankyrases are multidomain proteins. The C-terminal PARP domain catalyzes the poly-(ADP-ribosyl)ation of substrate proteins, whereas the ankyrin repeat domain interacts with the substrates and brings them to PARP domain. There are five ankyrin triple repeat clusters (ARCs) present in Tankyrase and, except ARC3, all are predicted to act as independent binding unit. The ARCs interact with substrates through their tankyrase binding motifs. All ARCs having similar substrate recognition abilities and the overall binding mode of substrates to an ARC of Tankyrase is highly conserved, with the binding peptide lying in a surface groove. Each ARC is able to bind the same set of proteins with different binding affinity. So they are redundant in function. The Tankyrase binding motif is usually depicted as RxxPDG. The arginine and glycine residues at positions 1 and 6 are highly conserved acting as critical anchor residues of the motif. The R enters the deepest part of the groove making charged interactions. The G is sandwiched in the narrowest part of the groove. The P and D positions are more variable. The motif is experimentally verified in nearly 17 proteins including 3BP2, AXIN1, TRF1, IRAP and NUMA1.
Pattern: .R..[PGAV][DEIP]G.
Pattern Probability: 0.0003538
Present in taxon: Metazoa
Interaction Domain:
Ank (PF00023) Ankyrin repeat (Stochiometry: 4 : 1)
PDB Structure: 3TWU
<a style="white-space:nowrap;" href="http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3TWU" target="_blank"><img src="/media/pdb.ico.png"/>3TWU</a>
o See 17 Instances for DOC_ANK_TNKS_1
o Abstract
Tankyrases are members of the poly (ADP-ribose) polymerases (PARPs). PARPs catalyze the linkage of ADP-ribose onto their substrates either as monomers or polymers using NAD+ as a source. Tankyrase is found in both the cytosol and nuclear compartments and is implicated in many important cellular functions ranging from telomere homeostasis and mitosis to vesicle trafficking (Zhang,2011). In mammals, the tankyrase protein family consists of tankyrase 1 and 2, which share 85% amino acid sequence identity. Tankyrases seem only be present in the metazoa (multicellular animals). The tissue expression of the tankyrases varies; TNKS is relatively abundant in reproductive tissues whereas the TNKS2 is more ubiquitous. Tankyrase 1 contains four distinct domains. The N-terminus contains the natively disordered HPS domain, followed by a long ankyrin repeat region. This region is clustered into five well conserved subdomains of three ANK repeats each, designated as ARC (ANK repeat cluster) 1-V. Each ARC domain is able to act as an independent unit and can interact with a variety of substrates possessing the sequence region known as the tankyrase binding motif. The SAM (sterile alpha motif) domain contributes to the multimerization of tankyrase 1. The C-terminal region encompasses the PARP domain, which catalyses poly-ADP-ribosylation of acceptor proteins using NAD+ as a substrate (Seimiya,2006). Tankyrase 2 has a similar modular organization as tankyrase1 but lacks the natively disordered HPS domain. Both tankyrases use the ankyrin modules to dock their substrates via their tankyrase binding motif. This motif consists of a minimum of six consecutive amino acids RxxPDG, where only the R and G are always conserved (Guettler,2011). Protein PARsylation can affect the fate of the protein through several ways including direct modulation of its activity, recruitment of binding partners that recognize poly(ADP-ribose) or by affecting protein turn over. Recent studies have shown that the mutation in the TNKS-binding motif of 3BP2 disrupts the interaction with Tankyrase and leads to cherubism in humans.
o 6 selected references:

o 12 GO-Terms:

o 17 Instances for DOC_ANK_TNKS_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Protein NameGene NameStartEndSubsequenceLogic#Ev.OrganismNotes
3BP2_HUMAN SH3BP2 414 421 PQLPHLQRSPPDGQSFRSFS TP 4 Homo sapiens (Human)
1 
BABA1_HUMAN BABAM1 47 54 AQASVGSRSEGEGEAASADD TP 3 Homo sapiens (Human)
1 
TERF1_HUMAN TERF1 12 19 SSAAPSPRGCADGRDADPTE TP 3 Homo sapiens (Human)
2 
FAT4_HUMAN FAT4 4826 4833 RRPLSRTRNPADGIPAPESS TP 3 Homo sapiens (Human)
1 
RAD54_HUMAN RAD54L 690 697 CVNSRQIRPPPDGSDCTSDL TP 3 Homo sapiens (Human)
1 
A9UF02_HUMAN BCR/ABL fusion 115 122 PAEEPEARPDGEGSPGKARP TP 3 Homo sapiens (Human)
1 
NUMA1_HUMAN NUMA1 1742 1749 SITSKLPRTQPDGTSVPGEP TP 2 Homo sapiens (Human)
1 
BABA1_HUMAN BABAM1 27 34 AEPRPRTRSNPEGAEDRAVG TP 3 Homo sapiens (Human)
1 
MCL1_HUMAN MCL1 77 84 PDSRRVARPPPIGAEVPDVT TP 1 Homo sapiens (Human)
1 
LCAP_HUMAN LNPEP 95 102 RNSATGYRQSPDGACSVPSA TP 3 Homo sapiens (Human)
1 
FNBP1_HUMAN FNBP1 514 521 VNNCAQDRESPDGSYTEEQS TP 4 Homo sapiens (Human)
2 
CASC3_HUMAN CASC3 145 152 KSTVTGERQSGDGQESTEPV TP 2 Homo sapiens (Human)
1 
AXIN1_HUMAN AXIN1 21 28 SFTEDAPRPPVPGEEGELVS TP 4 Homo sapiens (Human)
2 
TB182_HUMAN TNKS1BP1 1507 1514 RDSPPSWRPQPDGEASQTED TP 1 Homo sapiens (Human)
2 
DISC1_HUMAN DISC1 222 229 SLGSAGERGEAEGCPPSREA TP 3 Homo sapiens (Human)
1 
STRN_HUMAN STRN 301 308 EEGDNESRSAGDGTDWEKED TP 3 Homo sapiens (Human)
1 
FAT4_HUMAN FAT4 4571 4578 YGDDMTVRKQPEGNPKPDII TP 3 Homo sapiens (Human)
1 
Please cite: The Eukaryotic Linear Motif Resource ELM: 10 Years and Counting (PMID:24214962)

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