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case1278613018.pdf (2.72 MB)
ETD Abstract Container
Abstract Header
The Molecular Mechanisms Underlying Ligand Specificity of the Insulin and IGF-I Receptors
Author Info
Tao, Jia-Lin
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=case1278613018
Abstract Details
Year and Degree
2010, Doctor of Philosophy, Case Western Reserve University, Nutrition.
Abstract
The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGFR) are membrane bound receptors belonging to the IR superfamily. IR, stimulated by insulin, conducts signals resulting in energy homeostasis. Defect insulin secretion leads to type I diabetes mellitus; insufficient insulin signaling, usually due to insulin receptor resistance, results in type II diabetes mellitus. While, IGFR, bound to type 1 insulin-like growth factor (IGF-I), is responsible for the regulation of mitogenic and differentiating effects on most cell types. Excessive IGF-I-IGFR signaling are commonly found in biopsies from patients with cancer and in cultured immortalized cells. Although, structural similarities are found in between the ligands, insulin and IGFs, as well as their receptors, the IR and IGFR, the receptors bind insulin and IGFs with different affinities. Our goal is to identify and characterize determinants on the receptors responsible for ligand specificity, which allows us to understand the structure-function relationships of the IR and IGFR, their mechanisms of specific activation, which will ultimately lead to the design of novel IR agonists for diabetes therapy and IGFR antagonists for cancer therapy. In our investigations, we used chimeric IRs and IGFRs generated by site specific mutagenesis based on structural information from sequence alignments and crystallographic conformation comparison between the IRs and IGFRs. The ligand binding affinities were characterized by competition binding assays using radio-active isotope labeled insulin and IGF-I analogues. Several mutants based on the IR with deletion or charge reversal in the module 6 and the exon 11 displayed significant changes in binding affinity for IGF-I while retaining the affinity for insulin, indicating the importance of the module 6 and exon 11 in determining ligand specificity. From our data, we found that the major ligand specificity determinants reside in the regions with major structural difference and are complementary to the characteristics of their ligands, suggesting the structure-function relationship plays a core role in protein-protein interactions. Based on this principle and our findings, a chimeric IR with substitutions and deletions of twenty-five residues from the module 6 and exon 11 was generated and showed similar insulin affinity as the IR and similar IGF-I affinity as the IGFR, and thus, no specificity against either ligand.
Committee
Jonathan Whittaker, MD, PhD (Advisor)
Edith Lerner, PhD (Committee Chair)
Maria Hatzoglou, PhD (Committee Member)
Faramarz Ismail-Beigi, MD, PhD (Committee Member)
Danny Mannor, PhD (Committee Member)
Subject Headings
Biochemistry
Keywords
insulin
;
IGF
;
receptor
;
IGFBP
;
diabetes
;
cancer
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Citations
Tao, J.-L. (2010).
The Molecular Mechanisms Underlying Ligand Specificity of the Insulin and IGF-I Receptors
[Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1278613018
APA Style (7th edition)
Tao, Jia-Lin.
The Molecular Mechanisms Underlying Ligand Specificity of the Insulin and IGF-I Receptors.
2010. Case Western Reserve University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=case1278613018.
MLA Style (8th edition)
Tao, Jia-Lin. "The Molecular Mechanisms Underlying Ligand Specificity of the Insulin and IGF-I Receptors." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1278613018
Chicago Manual of Style (17th edition)
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Document number:
case1278613018
Download Count:
817
Copyright Info
© 2010, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.