First, the hydrophobic long N-terminal thumb in IGFBP3 (also in IGFBP5) provides local steric constraints on IGF1 C-domain loop, thus facilitating relocation and anchoring of the IGF1 C domain toward ALS in a suitable configuration (Figs. 2f and 7a). Here, IGF1 is linked to amyotrophic lateral sclerosis.