Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms

Louise Knudsen (1) , Pierre de Meyts , Vladislav V Kiselyov

1 Insulin and Incretin Biology

More than 20 years after the description of the two insulin receptor (IR) isoforms, designed IR-A (lacking exon 11) and IR-B (with exon 11) nearly every functional aspect of the alternative splicing both in vitro and in vivo remains controversial. In particular, there is no consensus on the precise ligand binding properties of the isoforms. Increased affinity and dissociation kinetics have been reported for IR-A in comparison to IR-B, but the reverse results have also been reported. These are not trivial issues considering the reported possible increased mitogenic potency of IR-A, and the reported link between slower dissociation and increased mitogenesis. We have re-examined the ligand binding properties of the two isoforms using a novel rigorous mathematical analysis based on the concept of a harmonic oscillator. We found unequivocally that insulin has 1.5 fold higher apparent affinity towards IR-A and a 2-fold faster overall dissociation rate. Analysis based on the model showed increased association (3-fold) and dissociation (2-fold) rate constants for binding site 1 of IR in comparison to IR-B. We also provide a structural interpretation of these findings based on the structure of the IR ectodomain and the proximity of the sequence encoded by exon 11 to the C-terminal peptide that is a critical trans-component of site 1.

Mots clés: Life Sciences

Louise Knudsen, Pierre de Meyts, Vladislav V Kiselyov. Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms. Biochemical Journal, 2011, 440 (3), pp.397-403. ⟨10.1042/BJ20110550⟩. ⟨hal-00658157⟩