Structural Analysis of Piezo1 Ion Channel Reveals the Relationship between Amino Acid Sequence Mutations and Human Diseases

Zikai Zhou

doi:10.4236/jbm.2019.712012

Abstract

Since first identified in 2010, Piezo proteins have been found to perform as poreforming mechanosensitive ion channels across a wide range of animals. As a Piezo ortholog primarily expressed in mammalian systems, Piezo1 has been observed to distribute mainly in nonsensory tissues, regulating osmotic homeostasis, proprioception, and light touch. With previous studies on the putative structure of Piezo1, the gating system and several mechanotransduction mechanisms have been proposed. Besides, mutations of specific amino acid sequences in Piezo1 have been linked to several human diseases such as dehydrated hereditary xerocytosis (DHS) and congenital lymphatic dysplasia (CLD). However, most of these mutations have not been well characterized. To further elucidate the relations between these mutations and diseases, UCSF Chimera is used as the tool to visualize the structural importance of each of these mutated amino acids. With the aid from UCSF Chimera, this study has recorded and interpreted clashes and contacts originated from each of the mutations. Accordingly, specific mechanisms between mutations and human diseases are proposed, which pave the way for healing.

Highlights

Piezo channels, first isolated and identified by scientists in 2010, primarily present in the form of two orthologs: Piezo1 and Piezo2, both contributing to the function of unique mechanosensitive channels [1]-[6]
Mutations of specific amino acid sequences in Piezo1 have been linked to several human diseases such as dehydrated hereditary xerocytosis (DHS) and congenital lymphatic dysplasia (CLD)
Each of these blades, deflecting at an angle of 100 degrees perpendicular to the membrane, constitutes several repeating amino acid bundles: or transmembrane helical units, within which are four transmembrane helices per Transmembrane helical units (THU) [8] [10] [11] [12]. To view these Piezo1 repeats more microscopically, the linkage between the first and the second and between the third and the fourth TMs, counted from the proximal to the distal end, are extracellular, whereas the linkage between the second and the third TMs is intracellular [11] [12] [13]. Those three blades all surround a central domain which is composed of one C-terminal domain (CTD), one “cap” or C-terminal extracellular domain (CED), three inner helices (IH), three outer helices (OH), and three anchors and latches [7]-[12]

Summary

Introduction

First isolated and identified by scientists in 2010, primarily present in the form of two orthologs: Piezo and Piezo, both contributing to the function of unique mechanosensitive channels [1]-[6]. It is shown that the Piezo channel exhibits a trimeric, propeller-like shape, with three identical blades extending out from the central pore in a rotatory manner [7]-[12] Each of these blades, deflecting at an angle of 100 degrees perpendicular to the membrane, constitutes several repeating amino acid bundles: or transmembrane helical units, within which are four transmembrane helices per THU [8] [10] [11] [12]. Piezo has been identified as an optimizer of human T cell activation and a prerequisite for bone formation (shown in Figure 1) [24] [42] Those disease-causing mutations are primarily linked to distortions near the central axis of Piezo, which indicates alterations in the pore module [43].

Sequence Alignment between hPiezo1 and mPiezo1

UCSF Chimera Analysis of the hPiezo1 Mutation Sites Using mPiezo1 Template

Structural Domains of Mutations and Contacts

Relationship between Mutations and Human Diseases

Findings

Conclusions