Mechanism of E-cadherin dimerization at the plasma membrane

Vu, Vinh

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https://hdl.handle.net/2142/110778 Copy

Description

Title

Mechanism of E-cadherin dimerization at the plasma membrane

Author(s)

Vu, Vinh

Issue Date

2021-03-26

Director of Research (if dissertation) or Advisor (if thesis)

Leckband, Deborah

Doctoral Committee Chair(s)

Leckband, Deborah

Committee Member(s)

• Zhang, Kai
• Das, Aditi
• Breiher, Bill

Department of Study

Biochemistry

Discipline

Biochemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Date of Ingest

2021-09-17T04:03:59Z

Keyword(s)

cadherin, fluorescence, dimerization, oligomerization

Abstract

Cadherins are essential intercellular adhesion proteins that regulate tissue cohesion and paracellular permeability by assembling dense adhesion plaques at cell-to-cell contacts. This thesis addresses two aspects of cadherin adhesion and force transduction. The first portion of this thesis addresses the mechanisms of E-cadherin dimerization at the plasma membrane and its impact on cadherin trans binding and on cadherin-mediated cell adhesion. Full-spectrum imaging fluorescence resonance energy transfer (FSI-FRET) measurements directly demonstrate that epithelial-cadherin (E-cadherin) forms constitutive lateral (cis) dimers at the plasma membrane. Studies further show that this requires the intracellular domain and binding to p120 catenin. Quantitative cell binding measurements and fluorescence imaging demonstrate that p120 catenin binding to the cadherin intracellular domain enhances the trans cadherin binding affinity, cell adhesion, and the assembly of macroscopic cadherin clusters at intercellular adhesions. Single-molecule tracking studies of engineered mutants of the E-cadherin ectodomain mutants on supported bilayers showed that the extracellular domain also clusters in the absence of the trans interaction or the intracellular domain, but the cis bonds between ectodomains are much weaker than those involving p120ctn. The second portion of this thesis described in Chapter 3 is on cadherin-based mechanotransduction and the role of homophilic vs heterophilic cadherin ligation on force transduction cascades. Studies demonstrate that cadherin force transduction requires homophilic cadherin ligation and cadherin association with specific receptor tyrosine kinases on the same cell. By contrast, heterophilic ligands fail to activate force transduction signaling. Studies further demonstrate that this mechano-selectivity regulates cadherin-dependent signaling cascades that reinforce cell adhesion strength and the extent of cell spreading on cadherin substrates. Overall, these studies provide novel insights into the assembly of cadherin adhesions, and the regulation of cadherin binding affinities, cell adhesion, and mechanotransduction.

Graduation Semester

2021-05

Type of Resource

Thesis

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http://hdl.handle.net/2142/110778

Copyright and License Information

Copy right 2021 Vinh Vu

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