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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.
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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.
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