Sequence Similarity among Structural Repeats in the Piezo Family of Mechanosensitive Ion Channels

Members of the Piezo family of mechanically activated cation channels are involved in multiple physiological processes in higher eukaryotes, including vascular development, cell differentiation, touch perception, hearing, and more, but they are also common in single-celled eukaryotic microorganisms. Mutations in these proteins in humans are associated with a variety of diseases, such as colorectal adenomatous polyposis, dehydrated hereditary stomatocytosis, and hereditary xerocytosis. 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 different repeats across Piezo homologs, (3) Piezo-specific conserved sequence signatures that consistently identify the same regions across repeats, and (4) conserved residues that maintain the same orientation and location in 3D space.