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Research article

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

Louise Knudsen, Pierre De Meyts, Vladislav V. Kiselyov
Biochemical Journal Nov 28, 2011, 440 (3) 397-403; DOI: 10.1042/BJ20110550
Louise Knudsen
Department of Insulin and Incretin Biology, Hagedorn Research Institute, Novo Nordisk A/S, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark
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  • For correspondence: lsek@novonordisk.com
Pierre De Meyts
Department of Insulin and Incretin Biology, Hagedorn Research Institute, Novo Nordisk A/S, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark
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Vladislav V. Kiselyov
Department of Insulin and Incretin Biology, Hagedorn Research Institute, Novo Nordisk A/S, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark
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Abstract

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.

  • binding kinetics
  • harmonic oscillator
  • insulin
  • insulin receptor
  • insulin receptor lacking exon 11 (IR-A)
  • insulin receptor with exon 11 (IR-B)
  • mathematical modelling

Abbreviations: a1, association rate constant of site 1; a2, association rate constant of site 2; CHO, Chinese-hamster ovary; d1, dissociation rate constant of site 1; d2, dissociation rate constant of site 2; ERK, extracellular-signal-regulated kinase; HBB, Hepes binding buffer; IGF, insulin-like growth factor; IGF-IR, type I IGF receptor; IR, insulin receptor; IR-A, IR lacking exon 11; IR-B, IR with exon 11; Kcr, cross-linking constant; MAPK, mitogen-activated protein kinase

  • © The Authors Journal compilation © 2011 Biochemical Society
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December 2011

Volume: 440 Issue: 3

Biochemical Journal: 440 (3)
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Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms
Louise Knudsen, Pierre De Meyts, Vladislav V. Kiselyov
Biochemical Journal Dec 2011, 440 (3) 397-403; DOI: 10.1042/BJ20110550
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Insight into the molecular basis for the kinetic differences between the two insulin receptor isoforms
Louise Knudsen, Pierre De Meyts, Vladislav V. Kiselyov
Biochemical Journal Dec 2011, 440 (3) 397-403; DOI: 10.1042/BJ20110550

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Keywords

binding kinetics
harmonic oscillator
insulin
insulin receptor
insulin receptor lacking exon 11 (IR-A)
insulin receptor with exon 11 (IR-B)
mathematical modelling

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