Fig. 6

Spatial and chromosome locations of significant Alzheimer’s disease signal variants in SORL1. PSCAN-M identified an AD signal region of 34 variants (out of a total of 214 considered) in SORL1. a SORL1’s structure contains a ten-bladed beta-propeller domain with a large tunnel at the center that binds peptides (PDB: 3WSY), top view (left) and side view (right). SORL1 binding of peptides, including amyloid-beta, is mediated by the L1 (dark orange) and L2 (green) loops from different blades near to the entrance of propeller binding tunnel. The dynamic 10CC domain wraps around the propeller upon binding; the 10CC-b region is colored blue. Signal region variants (purple spheres) cluster in 3D space in two functional sub-regions of SORL1: one side of the peptide binding tunnel and the 10CC region. Non-signal variants are indicated by cyan spheres. b Many of the signal variants are in close proximity to the ligand (yellow sticks); the side-chains of residues in contact with the ligand are shown as sticks. c Positions of the SORL1 variants on the segment of chromosome 11 for the SORL1 gene. Signal and non-signal variants are in purple and cyan, respectively