NDLI: Characterization of Ligand Binding of a Soluble Human Insulin-like Growth Factor I Receptor Variant Suggests a Ligand-induced Conformational Change

Content Provider	Journal of Biological Chemistry (JBC)
Author	Jansson, Magnus Hallén, Dan Koho, Hannu Andersson, Gunilla Berghard, Lotta Heidrich, Jessica Nyberg, Elisabeth Uhlén, Mathias Kördel, Johan Nilsson, Björn
Abstract	Details of the signal transduction mechanisms of the tyrosine kinase family of growth factor receptors remain elusive. In this work, we describe an extensive study of kinetic and thermodynamic aspects of growth factor binding to a soluble extracellular human insulin-like growth factor-I receptor (sIGF-IR) variant. The extracellular receptor domains were produced fused to an IgG-binding protein domain (Z) in transfected human 293 cells as a correctly processed secreted α-β′-Z dimer. The receptor was purified using IgG affinity chromatography, rendering a pure and homogenous protein in yields from 1 to 5 mg/liter of conditioned cell media. Biosensor technology (BIAcore) was applied to measure the insulin-like growth factor-I (IGF-I), des(1-3)IGF-I, insulin-like growth factor-II, and insulin ligand binding rate constants to the immobilized IGF-IR-Z. The association equilibrium constant, Ka, for the IGF-I interaction is determined to 2.8 × 108 M−1 (25 °C). Microcalorimetric titrations on IGF-I/IGF-IR-Z were performed at three different temperatures (15, 25, and 37 °C) and in two different buffer systems at 25 °C. From these measurements, equilibrium constants for the 1:1 (IGF-I:(α-β′-Z)2) receptor complex in solution are deduced to 0.96 × 108 M−1 (25 °C). The determined heat capacity change for the process is large and negative, −(1)0.51 kcal (K mol)−1. Further, the entropy change (ΔS) at 25 °C is large and negative. Far- and near-UV circular dichroism measurements display significant changes over the entire wavelength range upon binding of IGF-I to IGF-IR-Z. These data are all consistent with a significant change in structure of the system upon IGF-I binding.
Related Links	http://www.jbc.org/content/272/13/8189.abstract
Ending Page	8197
Starting Page	8189
Page Count	9
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	13
Volume Number	272
DOI	10.1074/jbc.272.13.8189
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1997-03-28
Access Restriction	Open
Subject Keyword	Protein Chemistry and Structure
Content Type	Text
Resource Type	Article
Subject	Molecular Biology Cell Biology Biochemistry

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