Crystal structure of the amino-terminal coiled-coil domain of the APC tumor suppressor

Coiled coils serve as dimerization domains for a wide variety of proteins, including the medically important oligomeric tumor suppressor protein, APC. Mutations in the APC gene are associated with an inherited susceptibility to colon cancer and with similar to 75 % of sporadic colorectal tumors. To define the basis for APC pairing and to explore the anatomy of dimeric coil ed coils, we determined the 2.4 Angstrom resolution X-ray crystal structure of the N-terminal dimerization domain of APC. The peptide APC-55, encompas sing the heptad repeats in APC residues 2-55, primarily forms an alpha-heli cal, coiled-coil dimer with newly observed core packing features. Correlate d asymmetric packing of four core residues in distinct, standard rotamers i s associated with a small shift in the helix register. At the C terminus, t he helices splay apart and interact with a symmetry-related dimer in the cr ystal to form a short, anti-parallel, four-helix bundle. N-terminal fraying and C-terminal splaying of the helices, as well as the asymmetry and helix register shift describe unprecedented dynamic excursions of coiled coils. The low stability of APC-55 and divergence from the expected coiled-coil fo ld support the suggestion that the APC dimerization domain may extend beyon d the first 55 residues. (C) 2000 Academic Press.