The ligand specificities of the insulin receptor and the insulin-like growth factor I receptor reside in different regions of a common binding site.
To identify the region(s) of the insulin receptor and the insulin-like growth factor I (IGF-I) receptor responsible for ligand specificity (high-affinity binding), expression vectors encoding soluble chimeric insulin/IGF-I receptors were prepared. The chimeric receptors were expressed in mammalian cells and partially purified. Binding studies revealed that a construct comprising an IGF-I receptor in which the 68 N-terminal amino acids of the insulin receptor alpha-subunit had replaced the equivalent IGF-I receptor segment displayed a markedly increased affinity for insulin. In contrast, the corresponding IGF-I receptor sequence is not critical for high-affinity IGF-I binding. It is shown that part of the cysteine-rich domain determines IGF-I specificity. We have previously shown that exchanging exons 1, 2, and 3 of the insulin receptor with the corresponding IGF-I receptor sequence results in loss of high affinity for insulin and gain of high affinity for IGF-I. Consequently, it is suggested that the ligand specificities of the two receptors (i.e., the sequences that discriminate between insulin and IGF-I) reside in different regions of a binding site with common features present in both receptors.
Kjeldsen
T
T
Molecular Genetics, Bioscience Corporate Research, Bagsvaerd, Denmark.
Andersen
A S
AS
Wiberg
F C
FC
Rasmussen
J S
JS
Schäffer
L
L
Balschmidt
P
P
Møller
K B
KB
Møller
N P
NP
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D005091:Exons; D006801:Humans; D007328:Insulin / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D007328:Insulin; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins; D011972:Receptor, Insulin