Transthyretin subdomain module and clusters. (A) The structure for the complete tetramer (pdb 1002), composed of four transthyretin monomers. (B) The sub-domain module, formed by three converging branches in the cluster tree (shown in light green in Figure 5) is shown in red. This module forms the dimer interface. Cluster B3 is shown in magenta in (B). Its importance is indicated by the fact that it straddles site 30, for which there is a well known val30met mutation that leads to misfolding and amyloidosis. This suggests that cluster B3, consisting of sites 29, 30 and 44 (B), has a critical roll in achieving a stable folded 3D structure. (C) Clusters D3 (labeled in yellow) and E3 (labeled in white) appear to be closely related. Each trio of mutually associated sites has remarkable symmetry, with one site at each end of the homotetramer channel, and one site in the center of the thyroxin binding site. The two residues at each end of both trios is likely important for the stabilization of the thyroxin pockets.