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Characterization of ligand binding of a soluble human insulin-like growth factor I receptor variant suggests a ligand-induced conformational change.
KTH, Superseded Departments, Biochemistry and Biotechnology.
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1997 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 272, no 13, 8189-8197 p.Article in journal (Refereed) Published
Abstract [en]

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 alpha-beta'-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 x 10(8) M-1 (25 degrees C). Microcalorimetric titrations on IGF-I/IGF-IR-Z were performed at three different temperatures (15, 25, and 37 degrees C) and in two different buffer systems at 25 degrees C. From these measurements, equilibrium constants for the 1:1 (IGF-I:(alpha-beta'-Z)2) receptor complex in solution are deduced to 0.96 x 10(8) M-1 (25 degrees C). The determined heat capacity change for the process is large and negative, -0.51 kcal (K mol)-1. Further, the entropy change (DeltaS) at 25 degrees 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.

Place, publisher, year, edition, pages
1997. Vol. 272, no 13, 8189-8197 p.
National Category
Industrial Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-13475PubMedID: 9079636OAI: oai:DiVA.org:kth-13475DiVA: diva2:325497
Note
QC 20100618Available from: 2010-06-18 Created: 2010-06-18 Last updated: 2011-11-08Bibliographically approved
In thesis
1. Structure-function analysis of insuline-like growth factor I interactions
Open this publication in new window or tab >>Structure-function analysis of insuline-like growth factor I interactions
1997 (English)Doctoral thesis, comprehensive summary (Other scientific)
Place, publisher, year, edition, pages
Stockholm: KTH, 1997. 69 p.
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-2490 (URN)91-7170-150-8 (ISBN)
Public defence
1997-04-01, 00:00
Note
QC 20100618Available from: 2000-01-01 Created: 2000-01-01 Last updated: 2011-11-08Bibliographically approved

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