Title

Structure and function relationship among the peptidyl prolyl cis/trans isomerases

Advisor

Gavini, Nara

Committee Member

Downer, Donald

Committee Member

Boyle, John

Committee Member

Pulakat, Lakshmi Devi

Committee Member

Peng, Zhaohua

Date of Degree

1-1-2007

Original embargo terms

MSU Only Indefinitely

Document Type

Dissertation - Open Access

Major

Biological Sciences

Degree Name

Doctor of Philosophy

College

College of Arts and Sciences

Department

Department of Biological Sciences

Abstract

Proteins exist in two conformers. The trans conformation is favored by the most of the amino acids. The proline residue due to its unique geometry has a high probability of being in the cis conformation. Thus the cis/trans isomerisation of the peptide bond preceding the proline residue becomes a rate limiting step in the folding and unfolding of the proteins. The enzymes which catalyze this rate limiting step were discovered by Fischer in porcine kidney and called as peptidyl prolyl cis trans isomerases (PPIases). There are four families of the PPIases. They are the parvulins, cyclophilins, FKBPs and trigger factors. All the four families catalyze a common reaction and the give rise to a stable trans product. We therefore wanted to analyse if cross complementation exists across the PPIase families. Our analysis has shown that the prokaryotic and the PPIase domain of the eukaryotic parvulins show a high structural similarity. The catalytic residues were found to be conserved across the genera. Our study has shown that a single domain 92 amino acid long prokaryotic parvulin PpiC from E.coli could complement for the function of Ess1 in Saacharomyces cerevisiae. We have also shown that under conditions of over expression the carboxy terminus of NifM from Azotobacter vinelandii could functionally replace Ess1 in S. cerevisiae. However the complete nifM was unable to do so. We have shown that the amino terminus of NifM acts as a regulatory unit not only for the PPIase activity of its carboxy terminus domain but also for the PPIase activity of PpiC and human Pin1. Using random mutagenesis we have identified the potential docking sites on amino terminus of NifM. These sites are defined as the residues which are responsible for the regulatory activity of NifM. Further we have found that FKBPs which show a high similarity with human Pin1 was unable to isomerise substrate specific to the parvulins. Our analysis has shown, the substrate binding pocket in FKBP is large due to its aromatic nature. Hence it is unable FKBPs to complement for the function of the parvulins.

Temporal Coverage

2000-2009

URI

https://hdl.handle.net/11668/16264

Comments

FKBPs||PPIases||Parvulins||Cross complementation

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