Our structural and biochemical analysis clearly shows that the N-terminal thumb of NBP3 as well as the ɑ3 helix and C-terminal loop of CBP3 are key determinants for assembly of ALS with specific binary complexes (IGF/IGFBP3 or IGF/IGFBP5). Here, IGFBP5 is linked to amyotrophic lateral sclerosis.