Structural Modes in Proteins: A Case Study in the PDZ Domain
| dc.contributor.advisor | Yu, Hongtao | en |
| dc.contributor.committeeMember | Ranganathan, Rama | en |
| dc.contributor.committeeMember | Gardner, Kevin H. | en |
| dc.contributor.committeeMember | Deisenhofer, Johann | en |
| dc.creator | Poole, Alan Matthew | en |
| dc.date.accessioned | 2017-01-03T21:43:50Z | |
| dc.date.available | 2017-01-03T21:43:50Z | |
| dc.date.created | 2014-12 | |
| dc.date.issued | 2014-11-20 | |
| dc.date.submitted | December 2014 | |
| dc.date.updated | 2017-01-03T21:38:20Z | |
| dc.description.abstract | Based on studies of protein structures, functional mutagenesis, allosteric control, and evolutionary records of proteins, we propose that proteins are built with an architecture of strong and weak interactions leading to the cooperative behavior of a few residues and the independence of many others. This pattern of heterogeneity determines many characteristics of proteins such as allosteric communication, enzymatic activity, and ligand-binding hot-spots. In addition, this architecture is likely to be a consequence of evolutionary selection and necessary in order to maintain viability while undergoing mutation and adaptation. Herein, I demonstrate the existence of a heterogeneous architecture in an individual protein (the third PDZ domain from rat PSD95) by measuring physical interactions between all pairs of residues. This global perturbation analysis is performed by making evolutionarily conservative mutations at every position in a protein and observing physical effects by monitoring a large number of NMR chemical shifts at nuclei distributed throughout the protein. The end result is a matrix of interactions between each mutation and all residues in the protein. Analysis of this chemical shift perturbation matrix reveals subsets of residues that interact strongly and cooperatively. These residues create structural modes that are present in the both free and peptide-bound PDZ3 and include many residues important for peptide-binding, suggesting that these structural modes are organized for the purpose of protein function. Furthermore, structural modes in PDZ3 are highly correlated with the protein sector identified by Statistical Coupling Analysis (SCA) -- a measure of residue coevolution -- in the PDZ domain family. This experiment produced a global map of physical interactions in the PDZ domain. The pattern of interactions is consistent with our model of a heterogeneous architecture composed of cooperative and independent residues. In addition, the correlation between structural modes and the SCA protein sector argues that cooperative physical interactions drive evolution in the PDZ domain family. The connection between physical features of individual proteins and statistical properties of protein families has significant applications for modeling complex physical behavior in proteins, for understanding the robustness and evolvability of natural systems, and for designing novel proteins. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 967597578 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/3937 | |
| dc.language.iso | en | en |
| dc.subject | Models, Structural | en |
| dc.subject | PDZ Domains | en |
| dc.subject | Proteins | en |
| dc.title | Structural Modes in Proteins: A Case Study in the PDZ Domain | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Molecular Biophysics | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |