Chemistry: molecular biology and microbiology – Enzyme – proenzyme; compositions thereof; process for... – Hydrolase
Reexamination Certificate
2001-05-25
2004-02-03
Prouty, Rebecca A. (Department: 1652)
Chemistry: molecular biology and microbiology
Enzyme , proenzyme; compositions thereof; process for...
Hydrolase
C435S320100, C435S287200, C435S325000, C435S419000, C435S252300, C435S254110, C536S023200, C536S023500
Reexamination Certificate
active
06686188
ABSTRACT:
The present application includes a Sequence Listing filed herewith on a single (CD-R) compact disc, provided in duplicate. The Sequence Listing is presented in a single file named “amended sequence.txt”, last modified Nov. 26, 2002 2:32:50 am, and having 2,312,956 bytes, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to a novel myosin-like protein particularly expressed in human heart and muscle, isolated nucleic acids encoding the myosin-like protein, compounds and compositions derivable directly or indirectly therefrom, and diagnostic and therapeutic methods for using the same.
BACKGROUND OF THE INVENTION
Myosins are ubiquitous proteins that act as intracellular engines, typically motoring along tracks of actin filaments within the cell to drive a variety of cellular processes including muscular contraction, cytokinesis, membrane trafficking and signal transduction. Baker et al.,
Curr. Opin. Cell Biol.
10: 80-86 (1998). Given the range of intracellular passengers and itineraries, some form of the myosin protein is found in virtually all eukaryotic cells.
The myosin gene superfamily has at least seventeen members, or classes, encoded by multiple genes.
Mammalian cells have the largest number of myosin genes, with the 28 identified myosin genes belonging to nine classes. Sellers,
Biochim. Biophys. Acta
1496: 3-22 (2000). The genome of the yeast,
Saccharomyces cerevisiae
, contains just 5 myosin genes. Brown,
Curr. Opin. Cell Biol.
9: 44-48 (1997). Between these extremes, the nematode
Caenorhabditis elegans
has 14 identified myosin genes. Baker et al.,
J. Mol. Biol.
172: 523-535 (1997). Myosins are also found in plant cells, with myosin genes in classes VIII, XI and XIII expressed exclusively in plants.
The structure of myosin always includes one or two heavy chains and several light chains.
The heavy chain is composed of three structurally and functionally different domains. The head domain, which is highly conserved across the myosin family, functions to generate force, and contains actin-binding and ATP-binding sites; the ATPase activity of the head domain is activated by actin binding. The neck region, which mediates association with the light chains, regulates the adjacent head domain. The tail domain regulates the specific activity of each myosin.
The light chains of myosin I and myosin V are calmodulin, which is a calcium-binding regulatory subunit in certain enzymes. Myosin II is also regulated by calcium-binding light chains, but not calmodulin.
Together, the disparate myosin heavy and light chains permit myosins to serve disparate cellular roles.
For example, in brush border microvilli, myosin I, one of the two most abundant forms of myosin, links the microfilament bundles to the plasma membrane.
Myosin II, the other of the two most abundant myosin classes, forms dimers in muscle cells that associate to form thick filaments, which are part of the contractile apparatus.
In addition to its well characterized role in contraction and force production in skeletal, cardiac, and smooth muscles, myosin II is required for cytokinesis, cell motility, cell polarity/chemotaxis, maintaining cell architecture and development in nonmuscle cells. Sellers,
Biochim. Biophys. Acta
1496:3-22 (2000).
Thus, contractile bundles, which comprise both actin and myosin II filaments, are found in numerous cell types. In epithelial cells, these bundles are called the circumferential belt and can function structurally (e.g., as an internal brace helping to control cell shape), or for motility (e.g., in wound healing, contraction seals the gap in a sheet of cells).
Myosin II is an integral component to the cytoskeletal substructure, acting to stiffen cortical membranes. In cytokinesis, myosin II plays an essential role performing the motor function for the contractile ring which constricts to form the cleavage furrow.
Myosin IXs, identified in rat, human and
C. elegans
, are expressed in a wide variety of tissues and cell types and are believed to be involved in intracellular signaling pathways. Myosin IX acts as a negative regulator of Rho (a G-protein), suggesting that it may control the Rho signaling pathways involved in cytoskeleton reorganization and other cellular processes. Bahler et al.,
Biochim. Biophys. Acta
1496:52-59 (2000). However the precise cellular functions of the myosin IXs and their exact roles in the Rho signaling pathways have still to be determined.
Membrane-bound myosins of various classes, particularly myosin I and myosin V, have been implicated in movement of vesicles within the cell. Due to its co-localization with Golgi membrane, myosin I is thought to move membrane vesicles between membrane compartments in the cytoplasm. Myosin I also serves as a membrane-microfilament linkage in microvilli.
In yet other examples of myosin function, protein secretion in yeast is disrupted by mutation in the myosin V gene, suggesting an important role for myosin V. In vertebrate brain tissue, myosin V is concentrated in the Golgi stacks and at the tips of membrane processes extending from neuronal cells. Espreafico et al.,
J. Cell Biol.
119: 1541 (1992). This type of membrane association would be consistent with the effects of myosin V mutations in mice, which adversely affect synaptic transmission, resulting in seizures and eventually death. In cell migration, different myosins localize to different regions of the cell. Myosin I localizes to the leading edge of a crawling amoeba, possibly participating in the translocation phase, whereas myosin II is more concentrated at the tail, where it is involved in retraction of the cell body.
Given their ubiquity, and the wide variety of tasks driven by myosins, it is not surprising that myosin defects have been implicated in a wide variety of diseases.
For example, as noted above, myosin V mutations in mice adversely affect synaptic transmission, resulting in seizures and eventually death.
Myosin and myosin-like genes have also been implicated in a number of human diseases.
For example, myosin plays a role in hypertrophic cardiomyopathy. An autosomally dominant form of the disease is frequently caused by a missense point mutation in exon 13 of the cardiac myosin heavy chain gene on chromosome 14. Less often, an abnormal cardiac myosin heavy chain hybrid gene is present.
As another example, mutation in the gene encoding myosin VIIA is responsible for some forms of Usher syndrome. Weil et al.,
Nature
374:60-61 (1995). Usher Syndrome is characterized by hearing impairment associated with retinitis pigmentosa.
Three classes of myosins, VI, VII and XV have been associated with genetic deafness disorders in mammals. Hasson,
Am. J. Hum. Genet.
61:801-5 (1997); Redowicz,
J. Muscle Res. Cell Mot.
20:241-248 (1999). Mutations in these myosins result in abnormalities in the stereocilia in the sensory cells of the inner ear of mice.
Other myosin-like genes may also be needed for normal stereociliary function in the inner ear, and mutations in these additional myosin-like genes may thus underlie or contribute to various forms of congenital deafness. For example, nonsyndromic hereditary deafness (DFNA17), mapped to chromosome 22q12.2-q13.3 in 1997, has now been associated with mutation in MYH9, a nonmuscle-myosin heavy-chain gene, located within the linked region. Lalwani et al.,
Am. J. Hum. Genet.
67:1121-8 (2000).
Despite the long-standing interest in myosins and sequence similarity among classes and across species, not all myosin and myosin-like genes have yet been identified, even in species that are genetically well characterized.
For example, a novel myosin-like gene (MysPDZ) has recently been cloned from mouse bone marrow stromal cells. The protein encoded by this newly identified gene contains a PDZ domain but no actin-binding domain. Furusawa et al.,
Biochem. Biophys. Res. Comm.
270: 67-75 (2000). PDZ domains are implicated in modular protein—protein interactions, also binding to specific C-terminal sequences of membrane proteins. Gee et al
Chen Wensheng
Gu Yizhong
Hanzel David Kagen
Ji Yonggang
Penn Sharron Gaynor
Amersham PLC
Becker Daniel M.
Fish & Neave
Prouty Rebecca A.
Roise David A.
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