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[摘要]：More than 20 years after the description of the two IR (insulin receptor) isoforms, designated 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 with IR-B, but the opposite 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 that insulin has 1.5-fold higher apparent affinity towards IR-A and a 2-fold higher 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 with IR-B. We also provide a structural interpretation of these findings on the basis of 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. |
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