Regulation of Nuclear bCatenin Activity 31 Structural Features of PCatenin

P-Catenin has two key cellular functions (Takemaru 2006). In cell adhesion, P-catenin binds type-I cadherins to mediate actin filament assembly via a-catenin at the plasma membrane (Gates and Peifer 2005; Huber and Weis 2001; Nelson and Nusse 2004; Pokutta and Weis 2000). In Wnt signaling, P-catenin acts as a co-activator through its interaction with an array of transcription factors and co-factors to regulate expression of target genes (Stadeli et al. 2006; Willert and Jones 2006).

Human or mouse P-catenin is 781 residues long and consists of a central structural core of 12 Armadillo (Arm) repeats flanked by unique N- and C-termini (Peifer et al. 1994) (Fig. 2). The central Arm repeat region is highly conserved across species. The crystal structure of this region reveals that each repeat consists of three a-helices, which pack tightly to form a highly elongated structure with a positively charged groove (Huber et al. 1997). Of note, many P-catenin-binding partners bind along the positively charged groove. Compared to the highly conserved Arm repeats, N- and C-terminal tails are diverged between Drosophila and vertebrate homologs. The structures of the N- and C-terminal domains are currently unknown and may not form a rigid structure by themselves. Nevertheless, these terminal domains have been shown to control a subset of protein-protein interactions

P-catenin Interactors

N-Terminal S/T

„ ^ . C-Terminal Activation Domain (C Activation Domain (NTAD) ^^^^^^

References

a-catenin

^ i i ^ i i

i i i i

Pokutta & Weis 2000

E-cadherin

i i

i i

Huber & Weis 2001

APC

i i

i i

Ha et al. 2004 Xing et al. 2004

i i

i i

Axin

i i

i i i i

Xing et al. 2003

Tcf/Lef

i i i i

i i i i i i

van de Wetering et al.1997 Graham et al. 2000 Graham et al. 2001

TBP

-

Hecht et al.1999

Lgs

i i i i

i i i

Kramps et al.2002 Holfmans & Basler 2004 Sampletro et al.2006

Pontin

i

Bauer et al. 1998

Brg1

i i i i

i i

Barker et al. 1998

CBP/p300

i i i i

i i

Hecht et al. 2000 Takemaru & Moon 2000

CoCoA

i i

Yang et al. 2006

TRRAP, ISWI, MLL

i i i i

i i

Slerra et al. 2006

Parafibromin

i i

Mosimann et al. 2006

MED12

i i i i

i i

Kim et al. 2006

ICAT

i i i i i i i i

i i i i i

Tago et al. 2000 Daniels & Wels 2002 Graham et al. 2002

Chibby

i i

Takemaru et al. 2003

Fig. 2 Schematic representation of P-catenin structure and its minimum domains required for protein-protein interactions with various partners. P-Catenin protein consists of 12 imperfect Armadillo (Arm) repeats (R1-12) flanked by N- and C-terminal tails. S/T represents serine/threonine residues phosphorylated by CKIa and GSK3. Two transcriptional activation domains are indicated by gray bars. Black lines denote interaction domains within P-catenin for the indicated binding partners

Fig. 2 Schematic representation of P-catenin structure and its minimum domains required for protein-protein interactions with various partners. P-Catenin protein consists of 12 imperfect Armadillo (Arm) repeats (R1-12) flanked by N- and C-terminal tails. S/T represents serine/threonine residues phosphorylated by CKIa and GSK3. Two transcriptional activation domains are indicated by gray bars. Black lines denote interaction domains within P-catenin for the indicated binding partners

(Castano et al. 2002; Choi et al. 2006; Solanas et al. 2004). Several P-catenin inter-actors require these domains for their binding as discussed further below.

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