The Stochastic Biophysics Controlling AQP4 Regulation and Self-Assembly
Abstract
Human aquaporin-4 (AQP4) is a channel protein that can transport up to 3 million water molecules per second, making it vital to water homeostasis and the collective movement of astrocyte endfeet under a variety of chemical cues working in concert with other co-expressed receptors and channel proteins (e.g., P2X7, TRPV4, Cx43, etc.). Particularly important is that AQP4s have two isoforms, which the AQP4-M23 isoform can assemble into well-defined square arrays called Orthogonal Arrays of Particles (OAPs). The sizes and shapes of these OAPs are highly regulated by the AQP4-M1 isoform and its palmitoylation state. Based on the assumption that different-sized OAPs control the biophysics of the cell, the central goals of this research are to determine a finite set of basic well-defined thermodynamic driving forces and concomitant dynamics that underlay the stochastic nature of OAP assembly-disassembly and explore how changes in palmitoylation state on AQP4-M1 subunits have a large effect on OAP size, AQP4 mobility, and AQP4 localization in astrocyte endfeet and that the AQP4 PDZ-domain also plays a key role in this context. The project goals will be met through six major objectives; (1) development of stable AQP4 monomers, (2) measurement of fundamental thermodynamic driving forces, (3) direct observation of the stochastic dynamics of protein-protein interactions and OAP formation, (4) building a membrane mimetic for the blood-brain barrier, (5) development of a simulation that embodies the stochastic nature of OAP formation and its thermodynamic boundaries, and (6) establish the palmitoylation states of AQP4 in astrocytes under hypoxia and oxygen-glucose-deprived (OGD) ischemic conditions. These objectives will be achieved through an international collaboration between Prof. James A. Brozik (Washington State University, USA) and Prof. Grazia Paola Nicchia (University of Bari, Italy).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 07, 2024
- Source ID
- FA95502310583
Entities
People
- James A Brozik
Organizations
- Air Force Office of Scientific Research
- United States Air Force
- Washington State University