Functional regulation via conformational dynamics is well known in
structured proteins, but less well characterized in intrinsically
disordered proteins and their complexes. Using NMR spectroscopy we have
identified a dynamic regulatory mechanism in the human insulin-like
growth factor (IGF) system involving the central, intrinsically
disordered linker domain of human IGF-binding protein-2 (
hIGFBP2). The bioavailability of IGFs is regulated by the
proteolysis of IGF-binding proteins. In the case of hIGFBP2, the
linker domain (L- hIGFBP2) retains its intrinsic disorder upon
binding IGF-1 but its dynamics are significantly altered, both in the
IGF binding region and distantly located protease cleavage sites. The
increase in flexibility of the linker domain upon IGF-1 binding may
explain the IGF-dependent modulation of proteolysis of IGFBP2 in this
domain. As IGF homeostasis is important for cell growth and function,
and its dysregulation is a key contributor to several cancers, our
findings open up new avenues for the design of IGFBP analogs inhibiting
IGF-dependent tumors.