Determinants of IGF-II influencing stability, receptor binding and activation
Insulin like growth factor II (IGF-II) is involved in metabolic and mitogenic signalling in mammalian cells and plays important roles in normal fetal development and postnatal growth.
IGF-II is structurally similar to insulin and binds to the type 1 insulin-like growth factor receptor (IGF-1R) and insulin receptor isoform A (IR-A) with high affinity. As IGF-II expression is commonly upregulated in cancer, an antagonist that blocks IGF-II action without perturbing insulin signalling would be highly valuable. The high degree of structural homology between the IR and IGF-1R makes selectively targeting either receptor in the treatment of IGF-II-dependent cancers challenging. However, sequence differences between insulin and IGF-II convey receptor selectivity and influence binding affinity and signalling outcome. Insulin residue YB16 is a key residue involved in maintaining insulin stability, dimer formation and IR binding. Mutation of this residue to glutamine (as found in IGF-II) reduces binding affinity. This study aimed to determine if the equivalent residue Q18 in IGF-II plays a similar role. Through site-directed mutagenesis of Q18, the authors found that this residue contributes to IGF-II structural integrity and selectivity of IGF-1R/IR binding, but surprisingly does not influence IR-A signalling activation. These findings provide insights into a unique IGF-II residue that can influence receptor binding specificity while having little influence on signalling outcome.