Date of Award
5-12-2024
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical and Chemical Engineering
Advisor(s)
Shikha Nangia
Second Advisor
Atanu Acharya
Keywords
Claudin;Molecular Dynamics;Stochastic sampling;Strand;Tight junction
Subject Categories
Chemical Engineering | Engineering
Abstract
Tight junctions, a form of cell junction, are utilized throughout the animal kingdom in one way or another. Tasked with facilitating a critical blockade between toxins and vital tissues while also allowing small crucial molecules to pass, the tight junction provides an important line of defense against disease. To build this barrier, various proteins with self-assemble within a cell membrane to then zipper with another cell membrane. The strand-like architecture and size & charge selective pore channels created within the barrier are chiefly governed by the claudin family of proteins. Without claudins present, the tight junction cannot form, and toxic molecules can flood into important barriers like the blood-brain barrier, the gastrointestinal tract, kidney nephrons, and others. To better understand the role claudins play in the tight junction, and complement experimental imaging data of claudin strands, this work describes three in silico approaches to better understand the components of the tight junction. Chapter 1 details the past three decades of experiments understanding claudin proteins, from the initial discovery and experimental understanding of claudin function to the solution of the first crystal structure and subsequent in silico studies. Chapter 2 details the prediction of a claudin-like protein’s structure and assembly in Hydra vulgaris, a freshwater invertebrate known for its regenerative ability. This work presented a novel claudin-like structure with a unique pore assembly not seen in human studies. Chapter 3 investigated the interaction between two tight junction proteins, JAM-A and ZO-2. This work provided further context to the importance of the C-terminal tail of tight junction proteins and the affinity ZO proteins possess to bind to membrane-embedded proteins like JAM-A. Chapter 4 describes an approach to predicting tight junction strand assembly using top claudin dimer conformations. This work provides a reproducible, yet stochastic process to quickly generate millions of claudin monomers, creating strands of over ten microns in length.
Access
Open Access
Recommended Citation
Marsch, Patrick Matthew, "Homomeric tight junction strand assembly of claudin proteins" (2024). Dissertations - ALL. 1916.
https://surface.syr.edu/etd/1916
