B48: Structural Transitions Modulate the Chaperone Activities of Grp94

Grp94 is a molecular chaperone found in the Heat shock protein (Hsp) 90 family. Grp94 is found in the endoplasmic reticulum and is a homodimer composed of a nucleotide-binding domain (NTD), middle domain (MD), and carboxyl-terminal domain (CTD). Heat shock proteins help maintain homeostasis in a cell that is under stress. Folded proteins become unfolded and aggregate when a cell is under stress, which can cause neurodegenerative disease. Additionally, these chaperones are involved in cellular processes such as signal transduction and protein trafficking. The inhibition of heat shock proteins or the absence of Grp94 disrupts signaling pathways. Therefore, Grp94 proteins have been used to target cancers to learn if signals that promote rapid cell division can be prevented. Similar to other Hsp90 chaperones, Grp94 undergoes a conformational cycle from an open to a closed state to fold client proteins in the cell. A Double Electron-Electron Resonance (DEER) spectroscopy experiment was performed to measure distances of the MTSSL nitroxide spin labels assigned to each protomer of Grp94. By using the known ATP 5ULS and ADP 2O1V structures of Grp94, molecular dynamics simulations were conducted to study the distances at positions K161 and R395 at different domains of the chaperone. The results showed some overlap in the distance distributions of the experimental and computational data. However, the experimental data had broader distance distributions because of the greater mobility in the spin label. Due to the time constraint of the computational simulations, there was not as much mobility in the spin label, which led to more narrow distributions. In the future, the distance distribution data from the MD simulations is expected to further aid in the modeling and understanding of the conformational changes in the Grp94 structure.

Author(s): Meghana Sugoor, Biology Major
Advisor(s): Andrea Kravats, Department of Chemistry and Biochemistry
Ikponwmosa Obaseki, Department of Chemistry and Biochemistry
Yaa Sarfowah Amankwah, Department of Chemistry and Biochemistry