Microbial Physiology Research Article Microbial Physiol 2023;33:49–62 DOI: 10.1159/000531468 Received: December 1, 2022 Accepted: June 5, 2023 Published online: June 15, 2023 Sequence Similarity among Structural Repeats in the Piezo Family of Mechanosensitive Ion Channels Kevin J. Hendargo a Ashay O. Patel a Onyeka S. Chukwudozie a Gabriel Moreno-Hagelsieb b J. Andrés Christen c Arturo Medrano-Soto a Milton H. Saier Jr. a a Department of Molecular Biology, School of Biological Sciences, University of California, San Diego, CA, USA; b Department of Biology, Wilfrid Laurier University, Waterloo, ON, Canada; c Departamento de Probabilidad y Estadística, Centro de Investigación en Matemáticas, CIMAT, Guanajuato, Mexico Keywords Ion channels · Piezo family · Repeat unit · Homology · Bioinformatics Abstract Members of the Piezo family of mechanically activated cation channels are involved in multiple physiological processes in higher eukaryotes, including vascular development, cell differ- entiation, touch perception, hearing, and more, but they are also common in single-celled eukaryotic microorganisms. Mu- tations in these proteins in humans are associated with a variety of diseases, such as colorectal adenomatous polyposis, dehydrated hereditary stomatocytosis, and hereditary xerocy- tosis. Available 3D structures for Piezo proteins show nine regions of four transmembrane segments each that have the same fold. Despite the remarkable similarity among the nine characteristic structural repeats in the family, no significant sequence similarity among them has been reported. Using bioinformatics approaches and the Transporter Classification Database (TCDB) as reference, we reliably identified sequence similarity among repeats based on four lines of evidence: (1) hidden Markov model-profile similarities across repeats at the family level, (2) pairwise sequence similarities between differ- ent repeats across Piezo homologs, (3) Piezo-specific conserved sequence signatures that consistently identify the same re- gions across repeats, and (4) conserved residues that maintain the same orientation and location in 3D space. © 2023 The Author(s). Published by S. Karger AG, Basel Introduction Multiple physiological processes respond to mechan- ical stimuli, including touch perception, pain sensation, hearing, and blood pressure regulation in animals. Me- chanosensitive ion channels of the Piezo family are critical for normal physiology and have been identified in vertebrates with homologs in invertebrates, plants, and protozoa [Coste et al., 2010; Kim et al., 2012; Moroni et al., 2018; Saotome et al., 2018]. Members of the Piezo family do not show sequence and structural similarities to any other known classes of ion channels, such as voltage- or ligand-gated channels [Kawate et al., 2009; Payandeh karger@karger.com www.karger.com/mip © 2023 The Author(s). Published by S. Karger AG, Basel Correspondence to: Milton H. Saier Jr., msaier @ ucsd.edu Arturo Medrano-Soto, l1medranosoto @ ucsd.edu This article is licensed under the Creative Commons Attribution- NonCommercial 4.0 International License (CC BY-NC) (http://www. karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission. Downloaded from http://karger.com/mip/article-pdf/33/1/49/3967290/000531468.pdf by guest on 22 July 2023