Theses and Dissertations

Issuing Body

Mississippi State University

Advisor

Fitzkee, Nicholas C.

Committee Member

Gwaltney, Steven R.

Committee Member

Mlsna, Todd E.

Committee Member

Mlsna, Debra A.

Committee Member

Emerson, Joseph P.

Date of Degree

12-1-2018

Document Type

Dissertation - Open Access

Degree Name

Doctor of Philosophy

College

College of Arts and Sciences

Department

Department of Chemistry

Abstract

Pin1 is an essential peptidyl-prolyl isomerase (PPIase) that catalyzes cis-trans prolyl isomerization in proteins containing phosphorylated serine/threonine-proline motifs (pSer/Thr-Pro). It has an N-terminal binding domain (WW) and a C-terminal PPIase domain. Pin1 targets pSer/Thr-Pro motifs by its WW domain and catalyzes isomerization through its PPIase domain. This dissertation is focused on elucidating the interactions between Pin1/substrate, the inter-domain dynamics upon binding, and the catalytic activity of Pin1 upon binding different substrates. Specifically, we investigated the Pin1-Histone H1 interaction and designed a series of chimeric peptides based on the H1.4 sequence (KATGAApTPKKSAKW). NMR titrations were performed for each peptide using both full-length Pin1 as well as the WW domain alone, to analyze the binding affinities. Here we combined 15N relaxation and residual dipolar couplings (RDCs) to monitor the degree to which peptide binding induced inter-domain interactions. We also investigated whether our chimeric sequences could alter catalysis (kex) using 1H-1H EXSY NMR experiments. Finally, when combined with molecular modeling, our results suggest a structural basis for how substrate binding can alter Pin1 inter-domain dynamics.

URI

https://hdl.handle.net/11668/20920

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