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Blood, 1 January 2005, Vol. 105, No. 1, pp. 161-169. Prepublished online as a Blood First Edition Paper on August 31, 2004; DOI 10.1182/blood-2004-06-2067. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-06-2067v1 105/1/161    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Franke, J. D. Articles by Kiehart, D. P. Search for Related Content PubMed PubMed Citation Articles by Franke, J. D. Articles by Kiehart, D. P. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cytoskeleton Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly Josef D. Franke, Fan Dong, Wayne L. Rickoll, Michael J. Kelley, and Daniel P. Kiehart From the Department of Biology, Developmental, Cell and Molecular Biology (DCMB) Group, Department of Cell Biology, and the Department of Medicine, Duke University Medical Center, Durham, NC; Hematology/Oncology, Durham Veterans Affairs Medical Center, Durham, NC; and Department of Biology, University of Puget Sound, Tacoma, WA. MYH9-related disorders are autosomal dominant syndromes, variably affecting platelet formation, hearing, and kidney function, and result from mutations in the human nonmuscle myosin-IIA heavy chain gene. To understand the mechanisms by which mutations in the rod region disrupt nonmuscle myosin-IIA function, we examined the in vitro behavior of 4 common mutant forms of the rod (R1165C, D1424N, E1841K, and R1933Stop) compared with wild type. We used negative-stain electron microscopy to analyze paracrystal morphology, a model system for the assembly of individual myosin-II molecules into bipolar filaments. Wild-type tail fragments formed ordered paracrystal arrays, whereas mutants formed aberrant aggregates. In mixing experiments, the mutants act dominantly to interfere with the proper assembly of wild type. Using circular dichroism, we find that 2 mutants affect the -helical coiled-coil structure of individual molecules, and 2 mutants disrupt the lateral associations among individual molecules necessary to form higher-order assemblies, helping explain the dominant effects of these mutants. These results demonstrate that the most common mutations in MYH9, lesions in the rod, cause defects in nonmuscle myosin-IIA assembly. Further, the application of these methods to biochemically characterize rod mutations could be extended to other myosins responsible for disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Kunishima, M. Hamaguchi, and H. Saito Differential expression of wild-type and mutant NMMHC-IIA polypeptides in blood cells suggests cell-specific regulation mechanisms in MYH9 disorders Blood, March 15, 2008; 111(6): 3015 - 3023. [Abstract] [Full Text] [PDF] J. D. Franke, R. A. Montague, W. L. Rickoll, and D. P. Kiehart An MYH9 human disease model in flies: site-directed mutagenesis of the Drosophila non-muscle myosin II results in hypomorphic alleles with dominant character Hum. Mol. Genet., December 15, 2007; 16(24): 3160 - 3173. [Abstract] [Full Text] [PDF] C. Leon, A. Eckly, B. Hechler, B. Aleil, M. Freund, C. Ravanat, M. Jourdain, C. Nonne, J. Weber, R. Tiedt, et al. Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion Blood, November 1, 2007; 110(9): 3183 - 3191. [Abstract] [Full Text] [PDF] Z. Chen, O. Naveiras, A. Balduini, A. Mammoto, M. A. Conti, R. S. Adelstein, D. Ingber, G. Q. Daley, and R. A. Shivdasani The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway Blood, July 1, 2007; 110(1): 171 - 179. [Abstract] [Full Text] [PDF] M. Martinelli, M. Di Stazio, L. Scapoli, J. Marchesini, F. Di Bari, F. Pezzetti, F. Carinci, A. Palmieri, P. Carinci, and A. Savoia Cleft lip with or without cleft palate: implication of the heavy chain of non-muscle myosin IIA J. Med. Genet., June 1, 2007; 44(6): 387 - 392. [Abstract] [Full Text] [PDF] S. Iwai, D. Hanamoto, and S. Chaen A Point Mutation in the SH1 Helix Alters Elasticity and Thermal Stability of Myosin II J. Biol. Chem., October 13, 2006; 281(41): 30736 - 30744. [Abstract] [Full Text] [PDF] D. D. Root, V. K. Yadavalli, J. G. Forbes, and K. Wang Coiled-Coil Nanomechanics and Uncoiling and Unfolding of the Superhelix and {alpha}-Helices of Myosin Biophys. J., April 15, 2006; 90(8): 2852 - 2866. [Abstract] [Full Text] [PDF] K. Reville, J. K. Crean, S. Vivers, I. Dransfield, and C. Godson Lipoxin A4 Redistributes Myosin IIA and Cdc42 in Macrophages: Implications for Phagocytosis of Apoptotic Leukocytes J. Immunol., February 1, 2006; 176(3): 1878 - 1888. [Abstract] [Full Text] [PDF] A. Pecci, I. Canobbio, A. Balduini, L. Stefanini, B. Cisterna, C. Marseglia, P. Noris, A. Savoia, C. L. Balduini, and M. Torti Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations Hum. Mol. Genet., November 1, 2005; 14(21): 3169 - 3178. [Abstract] [Full Text] [PDF] K.-Y. Kim, M. Kovacs, S. Kawamoto, J. R. Sellers, and R. S. Adelstein Disease-associated Mutations and Alternative Splicing Alter the Enzymatic and Motile Activity of Nonmuscle Myosins II-B and II-C J. Biol. Chem., June 17, 2005; 280(24): 22769 - 22775. [Abstract] [Full Text] [PDF]

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