Advisory Committee Chair
Bingdong Sha
Advisory Committee Members
Zsuzsanna Bebok
Peter Edward Prevelige
Jinbiao Ma
James Collawn
Document Type
Dissertation
Date of Award
2010
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
P58(IPK) is an endoplasmic reticulum (ER)-resident protein which is upregulated during unfolded protein response (UPR). In stressed cells, P58(IPK) functions to restore protein folding equilibrium in ER by suppressing protein aggregation and promoting protein folding. P58(IPK) associates with the unfolded protein via its N-terminal TPR domain and presents it to BiP (binding immunoglobulin protein) for subsequent folding. P58(IPK) belongs to the Hsp40 family. Collectively, P58(IPK) is a stress-inducible ER-resident molecular chaperone. In this dissertation, we report the crystal structure of P58(IPK) TPR domain to 2.5 Å resolution. In the crystal structure, the 43-kDa TPR domain consists of nine tandemly linked TPR motifs, termed TPR1 - TPR9. Three subdomains are readily identified which consist of TPR1-3, TPR4-6 and TPR7-9 respectively. All subdomains adopt similar folding which contains a groove in the center. The properties of the groove in each subdomain vary tremendously. Subdomain I groove residues are mostly hydrophobic and evolutionally conserved while subdomain II and III groove residues are negatively charged and variant among species. Structure-based mutagenesis suggests the groove in subdomain I is a potential binding site for unfolded protein. Mutation of the key residues in subdomain I groove (L48, Y71, Y75 and F104) abolishes P58(IPK) TPR domain's molecular chaperoning activity in vitro.
Recommended Citation
Tao, Jiahui, "Structural And Functional Study Of P58(Ipk)" (2010). All ETDs from UAB. 3103.
https://digitalcommons.library.uab.edu/etd-collection/3103
