Crowding-induced opening of the mechanosensitive Piezo1 channel in silico

Year: 2021

Type: article

Abstract: Mechanosensitive Piezo1 channels are essential mechanotransduction proteins in eukaryotes. Their curved transmembrane domains, called arms, create a convex membrane deformation, or footprint, which is predicted to flatten in response to increased membrane tension. Here, using a hyperbolic tangent model, we show that, due to the intrinsic bending rigidity of the membrane, the overlap of neighboring Piezo1 footprints produces a flattening of the Piezo1 footprints and arms. Multiple all-atom molecular dynamics simulations of Piezo1 further reveal that this tension-independent flattening is accompanied by gating motions that open an activation gate in the pore. This open state recapitulates experimentally obtained ionic selectivity, unitary conductance, and mutant phenotypes. Tracking ion permeation along the open pore reveals the presence of intracellular and extracellular fenestrations acting as cation-selective sites. Simulations also reveal multiple potential binding sites for phosphatidylinositol 4,5-bisphosphate. We propose that the overlap of Piezo channel footprints may act as a cooperative mechanism to regulate channel activity.

Source: Communications Biology

DOI: 10.1038/s42003-020-01600-1

Authors: Wenjuan Jiang, John Smith Del Rosario, Wesley Botello-Smith, Siyuan Zhao, Yi-chun Lin, Han Zhang, Jérôme Lacroix, Tibor Rohacs, Yun Lyna Luo

Institutions: Western University of Health Sciences, Rutgers New Jersey Medical School

Language: English

Topic: Erythrocyte Function and Pathophysiology

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

Open Access status: gold

Estimated APC paid: $3,290

Funders: National Science Foundation, U.S. Department of Health and Human Services, Western University of Health Sciences, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke

OpenAlex ID: W3122270077