Hypothetical model of the role of PS1 TMD1 in Aβ42 generation. (A and B) Alignment of amino acid residues of the human PS1 TMD1 and CLAC-P. In the swap mutant PS1, 82nd to 100th residues were replaced with CLAC-P TMD. Residues with similar side chains are labeled with asterisks in (A) and as yellow circles in (B). (C) Modified structural model of PS1 based on PSH structure kindly provided from Dr. Y. Shi . Side views of the ribbon model of TMD1, 6 and 7 generated by Pymol are shown. Yellow and purple residues correspond to those in (B). Possible approaches to the catalytic aspartates (red spheres) for Aβ40 and Aβ42 production lines are shown by yellow and purple arrows, respectively. TMD1 grips the substrate to prevent its liberation during the processive cleavage. Helix-helix interaction of longer Aβ with TMD1 determines the major production line (i.e., Aβ40 or Aβ42) of processive cleavage. (D) Top views of the whole PS1 model (left; ribbon diagram; right, surface model) generated by Pymol are shown. Putative substrate entry site  is shown as black arrows.