Evolution of allostery and conformational dynamics of caspases involved in the extrinsic pathway of apoptosis

Author

Mithun Nag Karadi Giridhar

ORCID Identifier(s)

0000-0003-0520-5921

Graduation Semester and Year

2023

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Quantitative Biology

Department

Biology

First Advisor

Clay Clark

Abstract

Caspases are a class of cysteine proteases that play a crucial role in programmed cell death (apoptosis). We complete an evolutionary picture of folding of caspases in the extrinsic pathway of apoptosis. The folding models show that the conformational free energy of the monomeric fold is conserved in the extrinsic pathway of apoptosis. In addition, with molecular dynamics and mass spectrometry we also show that the small subunit is less stable than the large subunit and charges destabilize allosteric regions in caspases allowing for dynamics. In order to gain insight into the evolution of allostery in caspases across different species, we employ an evolutionary strategy that combines experimental and computational methods. The findings provide mechanistic details of allostery in caspases, highlighting a highly conserved process that has evolved diverse mechanisms of packing hydrophobic residues in the core, which controls the architecture of the active site to fine-tune the specificity and activity of caspases. Further we identify residues and interactions that mediate allosteric regulation and substrate recognition, which has implications for the development of novel drugs to treat a wide range of diseases, including cancer and autoimmune disorders. Lastly, we show that amino acid evolution in the small subunit drives the evolution of varied oligomerization properties in initiator and effector subfamilies of the extrinsic pathway of apoptosis.

Keywords

Allostery, Protein folding, Thermodynamics, Conformational dynamics, Caspases

Disciplines

Biology | Life Sciences

License

This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.

Comments

Degree granted by The University of Texas at Arlington

Recommended Citation

Karadi Giridhar, Mithun Nag, "Evolution of allostery and conformational dynamics of caspases involved in the extrinsic pathway of apoptosis" (2023). Biology Dissertations. 157.
https://mavmatrix.uta.edu/biology_dissertations/157