Structural models of transthyretin and β2-microglobulin, protein-peptide docking models and sequence analysis. A) Ribbon diagrams of the monomeric subunits of transthyretin and β2-microglobulin are shown in green. The amyloidogenic β strands, F and D in transthyretin and β2-microgloublin respectively are in blue (McParland et al., 2000; Serag, Altenbach, Gingery, Hubbell, & Yeates, 2002; Thirumalai, Klimov, & Dima, 2003; Trinh, Smith, Kalverda, Phillips, & Radford, 2002). B) The 101HGKHEERQDE110 peptide from the loop region connecting β5 and β7 in the α crystallin core domain of human αB crystallin was docked with the crystal structures of transthyretin (left) and β2-microglobulin (right) using the ClusPro molecular docking program (Comeau, Gatchell, Vajda, & Camacho, 2004a, 2004b). Residues of the 101HGKHEERQDE110 sequence interact with residues of the F and D β strands of transthyretin and β2-microglobulin respectively. Interactions with the same residues in transthyretin and β2-microglobulin were observed when the 73DRFSVNLDVKHFS85 peptide which forms the β3 strand in the α crystallin core domain of αB crystallin was docked with the crystal structures of transthyretin and β2-microglobulin (data not shown). C) Sequence alignment of the amyloidogenic regions of transthyretin and β2-microglobulin with the primary sequences of Aβ1–42 and α-synuclein. The amyloidogenic regions of transthyretin and β2-microglobulin were aligned with the primary sequences of Aβ1–42 and α-synuclein using the DOTTER program (Miake, Mizusawa, Iwatsubo, & Hasegawa, 2002; Serag, Altenbach, Gingery, Hubbell, & Yeates, 2002; Sonnhammer & Durbin, 1995; Thirumalai, Klimov, & Dima, 2003; Trinh, Smith, Kalverda, Phillips, & Radford, 2002). Conserved residues are in blue. The grey box indicates encloses the residues that comprise the F and D β strands in transthyretin and β2-microglobulin. Residues 88–99, 49–59, 12–23, and 87–98 are the amyloidogenic fibril forming regions in transthyretin, β2-microglobulin, Aβ1–42, and α-synuclein respectively (Balbach et al., 2000; McParland et al., 2000; Miake, Mizusawa, Iwatsubo, & Hasegawa, 2002; Morimoto et al., 2004; Serag, Altenbach, Gingery, Hubbell, & Yeates, 2002; Thirumalai, Klimov, & Dima, 2003; Trinh, Smith, Kalverda, Phillips, & Radford, 2002). Structural analysis identified key interactions between amyloidogenic proteins and exposed peptides on the surface of the α crystallin core domain of human αB crystallin that account for modulation of fibril formation observed in the Thioflavin T assembly assays.