Impacts of Usher Syndrome Type IB Mutations on Human Myosin VIIa Motor Function†
- Shinya Watanabe
- ,
- Nobuhisa Umeki
- ,
- Reiko Ikebe
- , and
- Mitsuo Ikebe
Abstract
Usher syndrome (USH) is a human hereditary disorder characterized by profound congenital deafness, retinitis pigmentosa, and vestibular dysfunction. Myosin VIIa has been identified as the responsible gene for USH type 1B, and a number of missense mutations have been identified in the affected families. However, the molecular basis of the dysfunction of USH gene, myosin VIIa, in the affected families is unknown to date. Here we clarified the effects of USH1B mutations on human myosin VIIa motor function for the first time. The missense mutations of USH1B significantly inhibited the actin activation of ATPase activity of myosin VIIa. G25R, R212C, A397D, and E450Q mutations abolished the actin-activated ATPase activity completely. P503L mutation increased the basal ATPase activity for 2−3-fold but reduced the actin-activated ATPase activity to 50% of the wild type. While all of the mutations examined, except for R302H, reduced the affinity for actin and the ATP hydrolysis cycling rate, they did not largely decrease the rate of ADP release from actomyosin, suggesting that the mutations reduce the duty ratio of myosin VIIa. Taken together, the results suggest that the mutations responsible for USH1B cause the complete loss of the actin-activated ATPase activity or the reduction of duty ratio of myosin VIIa.
Cited By
This article is cited by 15 publications.
- Matthias Leung, Jeremy Steinman, Dorothy Li, Anjelynt Lor, Andrew Gruesen, Ahmed Sadah, Frederik J. van Kuijk, Sandra R. Montezuma, Altaf A. Kondkar, Rakesh Radhakrishnan, Glenn P. Lobo. The Logistical Backbone of Photoreceptor Cell Function: Complementary Mechanisms of Dietary Vitamin A Receptors and Rhodopsin Transporters. International Journal of Molecular Sciences 2024, 25 (8) , 4278. https://doi.org/10.3390/ijms25084278
- Joseph A. Cirilo, Xiayi Liao, Benjamin J. Perrin, Christopher M. Yengo. The dynamics of actin protrusions can be controlled by tip-localized myosin motors. Journal of Biological Chemistry 2024, 300 (1) , 105516. https://doi.org/10.1016/j.jbc.2023.105516
- Paulina Bahena, Narsis Daftarian, Reza Maroofian, Paola Linares, Daniel Villalobos, Mehraban Mirrahimi, Aboulfazl Rad, Julia Doll, Michaela A. H. Hofrichter, Asuman Koparir, Tabea Röder, Seungbin Han, Hamideh Sabbaghi, Hamid Ahmadieh, Hassan Behboudi, Cristina Villanueva-Mendoza, Vianney Cortés-Gonzalez, Rocio Zamora-Ortiz, Susanne Kohl, Laura Kuehlewein, Hossein Darvish, Elham Alehabib, Maria de la Luz Arenas-Sordo, Fatemeh Suri, Barbara Vona, Thomas Haaf. Unraveling the genetic complexities of combined retinal dystrophy and hearing impairment. Human Genetics 2022, 141 (3-4) , 785-803. https://doi.org/10.1007/s00439-021-02303-1
- Abhiraami Kannan-Sundhari, Denise Yan, Kolsoum Saeidi, Afsaneh Sahebalzamani, Susan H. Blanton, Xue Zhong Liu. Screening Consanguineous Families for Hearing Loss Using the MiamiOtoGenes Panel. Genetic Testing and Molecular Biomarkers 2020, 24 (10) , 674-680. https://doi.org/10.1089/gtmb.2020.0153
- Alessandro Terrinoni, Gerry Melino, Valeria Serra, Marco Alessandrini, Bianca Napolitano, Silvana Ciccarone, Alessia Lanzillotta, Ernesto Bruno. Deafness. 2018, 1-15. https://doi.org/10.1002/9780470015902.a0001453.pub3
- Osamu Sato, Satoshi Komatsu, Tsuyoshi Sakai, Yoshikazu Tsukasaki, Ryosuke Tanaka, Takeomi Mizutani, Tomonobu M. Watanabe, Reiko Ikebe, Mitsuo Ikebe. Human myosin VIIa is a very slow processive motor protein on various cellular actin structures. Journal of Biological Chemistry 2017, 292 (26) , 10950-10960. https://doi.org/10.1074/jbc.M116.765966
- Shzeena Dad, Nanna Dahl Rendtorff, Lisbeth Tranebjaerg, Karen Grønskov, Helena Gásdal Karstensen, Vigdis Brox, Øivind Nilssen, Anne-Françoise Roux, Thomas Rosenberg, Hanne Jensen, Lisbeth Birk Møller. Usher syndrome in Denmark: mutation spectrum and some clinical observations. Molecular Genetics & Genomic Medicine 2016, 4 (5) , 527-539. https://doi.org/10.1002/mgg3.228
- Violeta Mikštienė, Eglė Preikšaitienė, Algirdas Utkus. Hereditary hearing loss. Genetic factors in ethiopathogenesis of deafness. Medicinos teorija ir praktika 2014, 21 (1) , 55-64. https://doi.org/10.15591/mtp.2015.008
- Sarah M. Heissler, Dietmar J. Manstein. Functional characterization of the human myosin-7a motor domain. Cellular and Molecular Life Sciences 2012, 69 (2) , 299-311. https://doi.org/10.1007/s00018-011-0749-8
- Tsuyoshi Sakai, Nobuhisa Umeki, Reiko Ikebe, Mitsuo Ikebe. Cargo binding activates myosin VIIA motor function in cells. Proceedings of the National Academy of Sciences 2011, 108 (17) , 7028-7033. https://doi.org/10.1073/pnas.1009188108
- Jessica Haithcock, Neil Billington, Kevin Choi, Jennifer Fordham, James R. Sellers, Walter F. Stafford, Howard White, Eva Forgacs. The Kinetic Mechanism of Mouse Myosin VIIA. Journal of Biological Chemistry 2011, 286 (11) , 8819-8828. https://doi.org/10.1074/jbc.M110.163592
- Martin Schwander, Vanda Lopes, Anna Sczaniecka, Daniel Gibbs, Concepcion Lillo, David Delano, Lisa M. Tarantino, Tim Wiltshire, David S. Williams, Ulrich Müller. A Novel Allele of Myosin VIIa Reveals a Critical Function for the C-Terminal FERM Domain for Melanosome Transport in Retinal Pigment Epithelial Cells. The Journal of Neuroscience 2009, 29 (50) , 15810-15818. https://doi.org/10.1523/JNEUROSCI.4876-09.2009
- Amiel A. Dror, Karen B. Avraham. Hearing Loss: Mechanisms Revealed by Genetics and Cell Biology. Annual Review of Genetics 2009, 43 (1) , 411-437. https://doi.org/10.1146/annurev-genet-102108-134135
- Alessandro Terrinoni, Gerry Melino, Valeria Serra, Marco Alessandrini, Bianca Napolitano, Ernesto Bruno. Deafness. 2009https://doi.org/10.1002/9780470015902.a0001453.pub2
- Nobuhisa Umeki, Hyun Suk Jung, Shinya Watanabe, Tsuyoshi Sakai, Xiang-dong Li, Reiko Ikebe, Roger Craig, Mitsuo Ikebe. The tail binds to the head–neck domain, inhibiting ATPase activity of myosin VIIA. Proceedings of the National Academy of Sciences 2009, 106 (21) , 8483-8488. https://doi.org/10.1073/pnas.0812930106