Negative cooperativity in the insulin-like growth factor-I receptor and a chimeric IGF-I/insulin receptor.
Insulin and insulin-like growth factor-I (IGF-I) share a spectrum of metabolic and growth-promoting effects, mediated through homologous receptors that belong to the tyrosine kinase family. The dissociation rate of insulin from its receptor is affected by negative cooperativity, i.e. accelerates with increased receptor occupancy. The dose-response curve for the acceleration of tracer dissociation by unlabeled insulin has a distinct bell-shaped curve, with a progressive slowing down at insulin concentrations greater than 100 nM. The kinetics of the IGF-I interaction with its receptor has not been studied in such detail. In the present work, we report that while the IGF-I receptor exhibits negative cooperativity like the insulin receptor, the concentration dependence of the dissociation kinetics is distinct from that of native human insulin by not being bell-shaped, but monophasic like that of insulin analogues mutated at the hexamer-forming surface; it is changed to an insulin-type curve by substitution of IGF-I receptor's sequence including residues 382-565 with the homologous insulin receptor domain. The data suggest that like insulin, IGF-I has a bivalent binding mode and crosslinks two distinct areas of the two alpha subunits that are close, but distinct from the equivalent insulin receptor binding sites.
Hagedorn Research Institute, Gentofte, Denmark.
C T
CT
Christoffersen
K E
KE
Bornfeldt
C M
CM
Rotella
N
N
Gonzales
H
H
Vissing
R M
RM
Shymko
J
J
ten Hoeve
J
J
Groffen
N
N
Heisterkamp
P
P
De Meyts
D001158:Arteries / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D002678:Chimera; D006801:Humans; D007700:Kinetics; D015335:Molecular Probes / Q000235:genetics; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*
D015335:Molecular Probes; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin