Functional Consequences of the Piezo1 Membrane Footprint

Abstract

Piezos are mechanically activated ion channels that are necessary for many physiological functions, including the sensing of light touch and blood flow. Mutations in Piezos, furthermore, are implicated in more than ten human diseases. Piezos have been shown to adopt two conformational states: 1) a bowl-shaped closed conformation, which also induces extreme bending in the surrounding membrane over tens of nanometers and is thought to underlie Piezos’ high sensitivity to membrane tension; 2) a flat conformation, which may represent the open state, and does not induce substantial curvature in the surrounding membrane. Based on these observations, I sought to investigate the functional consequences of the membrane curvature induced by Piezos, which is also called the “Piezo footprint”. Specifically, I investigated 1) how do proteins known to induce or stabilize membrane curvature affect Piezo function and 2) how can the two Piezo conformations and footprint modulate the function of nearby membrane proteins? First, I discovered that Piezo mechanosensing function is generally robust to co-expression of many membrane-curving proteins, but I identified two homologous proteins that modulate Piezo1 kinetics. Second, I expanded on the finding that Piezo is capable of conformation signaling, or signal transduction by change in channel configuration that does not depend on ion permeation through the pore. I discovered that the Piezo footprint is a potential mechanism for conformational signaling. Together, these projects identify how the Piezo footprint can affect its mechanosensitivity and modulate neighboring membrane proteins.