JBM  Vol.7 No.12 , December 2019
Structural Analysis of Piezo1 Ion Channel Reveals the Relationship between Amino Acid Sequence Mutations and Human Diseases
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.
Cite this paper: Zhou, Z. (2019) Structural Analysis of Piezo1 Ion Channel Reveals the Relationship between Amino Acid Sequence Mutations and Human Diseases. Journal of Biosciences and Medicines, 7, 139-155. doi: 10.4236/jbm.2019.712012.

[1]   Xiao, R. and Xu, X.S. (2010) Mechanosensitive Channels: In Touch with Piezo. Current Biology, 20, R936-R938.

[2]   Coste, B., et al. (2010) Piezo1 and Piezo2 Are Essential Components of Distinct mechanically Activated Cation Channels. Science, 330, 55-60.

[3]   Coste, B., et al. (2012) Piezo Proteins Are Pore-Forming Subunits of Mechanically Activated Channels. Nature, 483, 176.

[4]   Alper, S. (2017) Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction. In: Current Topics in Membranes, Elsevier, Amsterdam, 97-134.

[5]   Parpaite, T. and Coste, B. (2017) Piezo Channels. Current Biology, 27, R250-R252.

[6]   Moroni, M., et al. (2018) Voltage Gating of Mechanosensitive PIEZO Channels. Nature Communications, 9, Article No. 1096.

[7]   Volkers, L., Mechioukhi, Y. and Coste, B. (2015) Piezo Channels: From Structure to Function. Pflügers Archiv: European Journal of Physiology, 467, 95-99.

[8]   Ge, J., et al. (2015) Architecture of the Mammalian Mechanosensitive Piezo1 Channel. Nature, 527, 64-69.

[9]   Guo, Y.R. and MacKinnon, R. (2017) Structure-Based Membrane Dome Mechanism for Piezo Mechanosensitivity. Elife, 6, e33660.

[10]   Saotome, K., et al. (2018) Structure of the Mechanically Activated Ion Channel Piezo1. Nature, 554, 481.

[11]   Zhao, Q., et al. (2018) Structure and Mechanogating Mechanism of the Piezo1 Channel. Nature, 554, 487-492.

[12]   Zhao, Q., et al. (2018) The Mechanosensitive Piezo1 Channel: A Three-Bladed Propeller-Like Structure and a Lever-Like Mechanogating Mechanism. The FEBS Journal, 286, 2461-2470.

[13]   Wang, Y., et al. (2018) A Lever-Like Transduction Pathway for Long-Distance Chemical- and Mechano-Gating of the Mechanosensitive Piezo1 Channel. Nature Communications, 9, Article No. 1300.

[14]   Jia, Z., et al. (2016) Regulation of Piezo2 Mechanotransduction by Static Plasma Membrane Tension in Primary Afferent Neurons. Journal of Biological Chemistry, 291, 9087-9104.

[15]   Borbiro, I., Badheka, D. and Rohacs, T. (2015) Activation of TRPV1 Channels Inhibits Mechanosensitive Piezo Channel Activity by Depleting Membrane Phosphoinositides. Science Signaling, 8, ra15.

[16]   Bavi, O., et al. (2016) Influence of Global and Local Membrane Curvature on Mechanosensitive Ion Channels: A Finite Element Approach. Membranes, 6, 14.

[17]   Wang, Y. and Xiao, B. (2018) The Mechanosensitive Piezo1 Channel: Structural Features and Molecular Bases Underlying Its Ion Permeation and Mechanotransduction. The Journal of Physiology, 596, 969-978.

[18]   French, A. (1992) Mechanotransduction. Annual Review of Physiology, 54, 135-152.

[19]   Wu, J., Lewis, A.H. and Grandl, J. (2017) Touch, Tension, and Transduction: The Function and Regulation of Piezo Ion Channels. Trends in Biochemical Sciences, 42, 57-71.

[20]   Pathak, M.M., et al. (2014) Stretch-Activated Ion Channel Piezo1 Directs Lineage Choice in Human Neural Stem Cells. Proceedings of the National Academy of Sciences, 111, 16148-16153.

[21]   Cinar, E., et al. (2015) Piezo1 Regulates Mechanotransductive Release of ATP from Human RBCs. Proceedings of the National Academy of Sciences, 112, 11783-11788.

[22]   Li, C., et al. (2015) Piezo1 Forms Mechanosensitive Ion Channels in the Human MCF-7 Breast Cancer Cell Line. Scientific Reports, 5, Article No. 8364.

[23]   Jin, Y., et al. (2014) Functional Role of Mechanosensitive Ion Channel Piezo1 in Human Periodontal Ligament Cells. The Angle Orthodontist, 85, 87-94.

[24]   Liu, C.S.C., et al. (2018) Cutting Edge: Piezo1 Mechanosensors Optimize Human T Cell Activation. The Journal of Immunology, 200, 1255-1260.

[25]   Shmukler, B.E., et al. (2015) Homozygous Knockout of the piezo1 Gene in the Zebrafish Is Not Associated with Anemia. Haematologica, 100, e483.

[26]   Ranade, S.S., et al. (2014) Piezo1, a Mechanically Activated Ion Channel, Is Required for Vascular Development in Mice. Proceedings of the National Academy of Sciences, 111, 10347-10352.

[27]   Martins, J.R., et al. (2016) Piezo1-Dependent Regulation of Urinary Osmolarity. Pflügers Archiv: European Journal of Physiology, 468, 1197-1206.

[28]   Rode, B., et al. (2017) Piezo1 Channels Sense Whole Body Physical Activity to Reset Cardiovascular Homeostasis and Enhance Performance. Nature Communications, 8, Article No. 350.

[29]   Faucherre, A., et al. (2014) Piezo1 Plays a Role in Erythrocyte Volume Homeostasis. Haematologica, 99, 70-75.

[30]   Ma, S., et al. (2018) Common PIEZO1 Allele in African Populations Causes RBC Dehydration and Attenuates Plasmodium Infection. Cell, 173, 443-455e12.

[31]   Fotiou, E., et al. (2015) Novel Mutations in PIEZO1 Cause an Autosomal Recessive Generalized Lymphatic Dysplasia with Non-Immune Hydrops Fetalis. Nature Communications, 6, Article No. 8085.

[32]   Nonomura, K., et al. (2018) Mechanically Activated Ion Channel PIEZO1 Is Required for Lymphatic Valve Formation. Proceedings of the National Academy of Sciences, 115, 12817-12822.

[33]   Lukacs, V., et al. (2015) Impaired PIEZO1 Function in Patients with a Novel Autosomal Recessive Congenital Lymphatic Dysplasia. Nature Communications, 6, Article No. 8329.

[34]   Lee, W., et al. (2014) Synergy between Piezo1 and Piezo2 Channels Confers High-Strain Mechanosensitivity to Articular Cartilage. Proceedings of the National Academy of Sciences, 111, E5114-E5122.

[35]   Bae, C., et al. (2013) Xerocytosis Is Caused by Mutations That Alter the Kinetics of the Mechanosensitive Channel PIEZO1. Proceedings of the National Academy of Sciences, 110, E1162-E1168.

[36]   Demolombe, S., et al. (2013) Slower Piezo1 Inactivation in Dehydrated Hereditary Stomatocytosis (Xerocytosis). Biophysical Journal, 105, 833.

[37]   Glogowska, E., et al. (2017) Novel Mechanisms of PIEZO1 Dysfunction in Hereditary Xerocytosis. Blood, 130, 1845-1856.

[38]   Andolfo, I., et al. (2015) Novel Gardos Channel Mutations Linked to Dehydrated Hereditary Stomatocytosis (Xerocytosis). American Journal of Hematology, 90, 921-926.

[39]   Zarychanski, R., et al. (2012) Mutations in the Mech-anotransduction Protein PIEZO1 Are Associated with Hereditary Xerocytosis. Blood, 120, 1908-1915.

[40]   Sandberg, M., et al. (2014) Hereditary Xerocytosis and Familial Haemolysis Due to Mutation in the PIEZO1 Gene: A Simple Diagnostic Approach. International Journal of Laboratory Hematology, 36, e62-e65.

[41]   Romac, J.M.-J., et al. (2018) Piezo1 Is a Mechanically Activated Ion Channel and Mediates Pressure Induced Pancreatitis. Nature Communications, 9, Article No. 1715.

[42]   Sun, W., et al. (2019) The Mechanosensitive Piezo1 Channel Is Required for Bone Formation. eLife, 8, e47454.

[43]   Gnanasambandam, R., Gottlieb, P.A. and Sachs, F. (2017) The Kinetics and the Permeation Properties of Piezo Channels. Current Topics in Membranes, 79, 275-307.

[44]   Wu, J., Goyal, R. and Grandl, J. (2016) Localized Force Application Reveals Mechanically Sensitive Domains of Piezo1. Nature Communications, 7, Article No. 12939.

[45]   Cox, C.D., et al. (2016) Removal of the Mechanoprotective Influence of the Cytoskeleton Reveals PIEZO1 Is Gated by Bilayer Tension. Nature Communications, 7, Article No. 10366.

[46]   Nourse, J.L. and Pathak, M.M. (2017) How Cells Channel Their Stress: Interplay between Piezo1 and the Cytoskeleton. Seminars in Cell & Developmental Biology, 71, 3-12.

[47]   Janmey, P. and Kinnunen, P. (2006) Biophysical Properties of Lipids and Dynamic Membranes. Trends in Cell Biology, 16, 538-546.

[48]   Lewis, A.H. and Grandl, J. (2015) Mechanical Sensitivity of Piezo1 Ion Channels Can Be Tuned by Cellular Membrane Tension. Elife, 4, e12088.

[49]   Pliotas, C., et al. (2015) The Role of Lipids in Mechanosensation. Nature Structural & Molecular Biology, 22, 991.

[50]   Lolicato, M., et al. (2014) Transmembrane Helix Straightening and Buckling Underlies Activation of Mechanosensitive and Thermosensitive K2P Channels. Neuron, 84, 1198-1212.

[51]   Delaunay, J. (2004) The Hereditary Stomatocytoses: Genetic Disorders of the Red Cell Membrane Permeability to Monovalent Cations. Seminars in Hematology, 41, 165-172.

[52]   Shussman, N. and Wexner, S.D. (2014) Colorectal Polyps and Polyposis Syndromes. Gastroenterology Report, 2, 1-15.