Researchers Discover A New Driver of Membrane Curvature

David Busch

David Busch, a postdoctoral fellow working with Professor Jeanne Stachowiak, was the lead author on the Nature Communications paper.

Researchers from the Department of Biomedical Engineering at the University of Texas at Austin have discovered a previously unrecognized mechanism for how cells regulate the shape and content of their membranes. The team, led by Professor Jeanne Stachowiak, recently published their findings in Nature Communications.

The cell membrane is a fundamental organelle of all cells that is critical for separating from and communicating with the outside environment. Membrane curvature is essential to many cellular processes including the internalization of signaling receptors and key nutrients. The prevailing view has been that structured protein motifs such as amphipathic helices, or crescent-shaped BAR domains, have been the drivers of membrane curvature. However, Dr. Jeanne Stachowiak's group now reports the unexpected finding that proteins without any defined structure—intrinsically disordered protein domains—are potent drivers of membrane curvature.

Intrinsically disordered proteins have largely been ignored in the context of membrane bending because they lack a defined structure, and were thought to be simply flexible linkers attached to the curvature-promoting wedge and BAR domains of proteins. However, Stachowiak's group which includes postdoctoral researcher and lead author David Busch, together with alum Justin Houser were able to demonstrate that these disordered domains are actually more efficient at driving curvature than the traditional wedge domains.

Stachowiak's group showed that the high efficiency of bending is driven by a mechanism of protein crowding. Intrinsically disordered proteins occupy more space than structured proteins, such that when they bind a membrane surface they are able to efficiently crowd and bend that membrane.

crowding of membranes

The crowding of molecules on a cellular membrane (shown in tan) drives the bending of that membrane toward the crowded surface. Small-structured proteins (shown in blue) can drive this crowding, but proteins without structure, intrinsically disordered proteins (IDPs), occupy a larger area and therefore more efficiently crowd and bend membrane surfaces.

illustrated diagram of Clathrin in cell

Clathrin (shown in magenta) is one of many proteins that cells use to bend and internalize their membranes. This internalization depends on a balance of pressures between the crowded intracellular proteins, such as large IDPs, and the crowding of extracellular cargo proteins (shown in green).

The study focused on the outermost cell membrane, but cells also have many internal membranes. Membrane vesicles move continuously inside cells to traffic molecules between cellular compartments.

Stachowiak would next like to perform similar experiments to determine if intrinsically disordered proteins also drive membrane curvature in these internal membrane systems. She says that the next steps to build on this research include studying the trafficking of transmembrane proteins, which are defective in specific forms of human diseases. Further defining the physical mechanisms that regulate membrane curvature and protein traffic will ultimately improve our understanding of cellular biology as well as the treatment of specific human diseases.

Other authors on the study include Senior Research Fellow Carl Hayden, Professor Eileen Lafer at UT Health Sciences Center in San Antonio, and collaborator Michael Sherman at the University of Texas Medical Branch, Galveston.