GRP78 and cell-surface GRP78 self-association; In silico perspective

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Cell surface glucose-regulated protein 78 (cs-GRP78) is implicated as a receptor for various infectious agents.
• Understanding GRP78's cellular localization is crucial for elucidating pathogen recognition mechanisms.

Purpose of the Study:

• To investigate the structural stability and membrane interactions of the homodimeric form of GRP78.
• To explore the role of GRP78 in cellular membrane permeability and pathogen entry.

Main Methods:

• Utilized a combination of bioinformatics tools, molecular docking, and molecular dynamics simulations.
• Simulated GRP78 homodimer in both aqueous solution and within a lipid bilayer membrane over 100 ns.

Main Results:

• GRP78 dimer demonstrated stability in both aqueous and membrane environments.
• The membrane-bound GRP78 dimer exhibited reduced fluctuations in substrate binding domains compared to the aqueous state.
• A stable 12 Å diameter pore formed by the GRP78 dimer in the membrane, remaining open throughout the simulation.

Conclusions:

• The GRP78 dimer is stable within the cell membrane, potentially due to reduced domain fluctuations.
• The formation of a persistent pore by GRP78 enhances membrane permeability.
• This pore formation mechanism may explain cs-GRP78's role in facilitating the internalization of hydrophobic molecules.