Given the conserved three hydrophobic residues at positions 2, 3, and 6 with respect to the first N-terminal Cys residue (L7, V10, and V11 for IGFBP3; L1, F4, and V5 for IGFBP5) (Supplementary Fig. 3b), we speculate that the NBP5 thumb would similarly be involved in the relocation of the IGF1 C-domain loop toward a more suitable position for interaction with ALS. Here, IGFBP3 is linked to amyotrophic lateral sclerosis.