Symmetric signaling by an asymmetric 1 erythropoietin : 2 erythropoietin receptor complex
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302346628-MIT.pdf
Description
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4.13 MB
Format
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Checksum (MD5)
9010da3b7f6a4043cf909ab53a7d7a6e
Author(s)
Zhang, Yingxin
Advisor(s)
Harvey F. Lodish.
Date Issued
2008
Publisher
Massachusetts Institute of Technology
Abstract
One erythropoietin molecule binds asymmetrically to two identical receptor monomers via erythropoietin site 1 and site 2, although it is unclear how asymmetry affects receptor activation and signaling. Here we report the computational design and experimental validation of two mutant erythropoietin receptors: one that binds only to erythropoietin site 1 but not site 2, and one that binds only to site 2 but not site 1. Expression of either mutant receptor alone in Ba/F3 cells cannot elicit a signal in response to erythropoietin, but when co-expressed, there is a proliferative response and activation of the JAK2 Stat5 signaling pathway. A truncated erythropoietin receptor with only one cytosolic tyrosine (Y343), on only one receptor monomer is sufficient for signaling in response to erythropoietin, regardless of the monomer on which it is located. The same results apply to having only one conserved juxtamembrane hydrophobic L253 or W258 residue, essential for JAK2 activation, in the full-length receptor dimer. We conclude that despite asymmetry in the ligand-receptor dimer interaction, both sides are competent for signaling, and we suggest that the receptors signal equally.
Description
Thesis (M. Eng.)--Massachusetts Institute of Technology, Biological Engineering Division, 2008.
Includes bibliographical references (p. 43-46).
Subjects
Biological Engineering Division.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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