Dimer formation by an N-terminal coiled coil in the APC protein.

Abstract

Mutations in the human APC gene are associated with an inherited predisposition to colon cancer. APC codes for polypeptides of =2800 amino acids, with sequence homologies to coiled-coil proteins in the first 900 residues. To determine the oligomerization properties of the APC protein, we used genetic and biochemical approaches to examine the ability of APC fragments to self-associate. A subdomain comprising the first 55 amino acids of APC was found to form a stable, parallel, helical dimer, as expected for a coiled coil. The location of a key dimerization element at the N terminus of the protein supports models in which mutations in APC exert effects through dimerization of the mutant gene products.

Novel protein isoforms of the APC tumor suppressor in neural tissue

“…We have shown that the BS ± APC isoforms do not interact with APC isoforms that contain exon 1-encoded sequence (Figure 3), or the homodimerization domain Joslyn et al, 1993). It is not clear why cells require such a diversity of APC isoforms, but the presence of such isoforms with selected domains may make these di erent isoforms functional`specialists'.…”

“…Immunoprecipitates from rat cerebrum using BS antibody (lane 1, BS) or Ab-5 (lane 2, Ab-5) were labeled with a b-catenin monoclonal antibody to determine if BS ± APC protein interacted with b-catenin. BS ± APC protein isoforms lack exon 1-encoded sequences involved in homodimerization (Joslyn et al, 1993;Su et al, 1993a). Therefore, we determined whether BS ± APC interacted with the exon 1-15-encoded APC.…”

“…APC protein has been localized to the advancing edge of the lamellipodia in ®broblasts suggesting a role in cell migration (Nathke et al, 1996). The role of the conventional APC protein in these functions may depend upon homodimerization (Joslyn et al, 1993;Su et al, 1993a), mediated through a series of heptad repeats in the amino terminal domain of APC; the ®rst heptad repeat of this dimerization domain is encoded by exon 1 Joslyn et al, 1993). Proteins predicted by the sequence of RNA transcripts containing the novel 5' exons of APC do not contain the exon 1-encoded homodimerization domain, and are not as likely to form coiledcoil structures (Santoro and Groden, 1997).…”

Secondary structure of an armadillo single repeat from the APC protein

“…Most of the APC gene alterations are located downstream of a ~even tandem arm repeat region (residues 452-767, see Fig. 1) Until now only very little is known about structural aspests of the APC protein except for a coiled coil domain fo "med by the N-terminal amino acids 1-55 [9].…”

Cilia, adenomatous polyposis coli and associated diseases

“…The N-terminal of APC protein is a homo-dimers oligomerized and formed by heptad repeats with coiled structure. The existence of 6-57 amino acids has a significant part in oligomerization (Joslyn et al, 1993). The armadillo region consists of seven repeats among residues of 453-767.…”