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Department of Biochemistry and Molecular Biology University of Nebraska Medical Center Omaha, Nebraska 68198-4525
Insulin-like growth factor II (IGF-II) and
phosphomannosylated glycoproteins bind to distinct sites on the same
receptor, the IGF-II/mannose 6-phosphate receptor (IGF2R). Analysis of
truncated receptors (minireceptors) has been used to map the IGF-II
binding site within the receptor’s extracytoplasmic domain, which
consists of 15 homologous repeats. A minireceptor consisting of repeat
11 contained the minimal elements for binding IGF-II, but with 5- to
10-fold lower relative binding affinity than the full-length receptor.
We hypothesized that the complete, high-affinity IGF-II binding site is
formed by interaction between the primary site in repeat 11 and a
putative affinity-enhancing domain. To determine the minimum portion of
the IGF2R’s extracytoplasmic domain needed for expression of
high-affinity IGF-II binding, a nested set of FLAG epitope-tagged
minireceptors encompassing repeats 11 through 15 was prepared and
transiently expressed in 293T cells. Minireceptors containing repeats
11–13 or 11–15 exhibited high affinity, comparable to the full-length
receptor (IC50 = 1–2
nM), whereas constructs containing repeat 11
only or repeats 11–12 did not (IC50 = 10–20
nM). These data suggested that the
affinity-enhancing domain is located within repeat 13, which contains a
unique 43-residue insert that has 
50% sequence identity to the type
II repeat of fibronectin. Although a repeat 13 minireceptor did not
bind IGF-II on its own, an 11–13 minireceptor containing a deletion of
the 43-residue insert exhibited low IGF-II binding affinity
(IC50 = 10–20 nM).
Expression of mutant receptors from a full-length IGF2R construct
bearing a deletion of the 43-residue insert was very low relative to
wild type. Depletion assays using IGF-II-Sepharose showed that the
mutant receptor had lower affinity for IGF-II than the wild-type
receptor. This study reveals that two independent receptor domains are
involved in the formation of a high-affinity binding site for IGF-II,
and that a complete repeat 13 is required for high-affinity IGF-II
binding.
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