Mammalian hyaluronidases hydrolyze hyaluronan, a polysaccharide of diverse physiological roles found in all tissues and body fluids. In addition to its function in normal cellular hyaluronan turnover, human hyaluronidase-1 is implicated in cancer proliferation, angiogenesis, and inflammatory diseases; its expression is up-regulated in advanced stages of bladder cancer, whereas the expression of the alternative splice-variants is down-regulated. The crystal structure reveals a molecule composed of two closely associated domains: a catalytic domain that adopts a distorted ( /R) 8 barrel resembling that of bee venom hyaluronidase, and a novel, EGF-like domain, characteristic of involvement in protein-protein interactions and regulatory processes. The structure shows that the fold of this unique EGF-like domain is intact in four alternative splice-variants, whereas the catalytic domain is likely to be unfolded. Thus, these variants may function by competing with the full-length enzyme for the putative protein partner and regulating enzymatic activity in healthy cells.Hyaluronan (HA 1 ) is a linear, unsulfated, negatively charged, glycosaminoglycan formed from ∼2000-25000 repeating disaccharide units of D-glucuronic acid (GlcUA) and N-acetyl-D-glucosamine (GlcNAc) with [GlcUA-( 1f3)-GlcNAc-( 1f4)] n linkages. HA is the major component of cartilage and serves as a joint lubricant. It controls water homeostasis in tissues and the extracellular matrix, which affects cell motility and the distribution and transport of plasma proteins. HA is also implicated in cell proliferation, differentiation, cell-cell recognition, tumor growth and invasion, angiogenesis, and inflammatory responses (1-3). The cellular role of HA and the HA-mediated signal transduction pathways depends on its size (recently reviewed by Stern et al. (4)). Large HA polymers function in organizing the extracellular matrix and serve as lubricant and shock absorber. In shock, septicemia, post surgery, blood loss, and burns, the level of circulating high molecular mass HA increases. These HA polymers are antiangiogenic, immunosuppressive, and anti-inflammatory. In contrast, HA fragments of intermediate sizes are involved in the body's alarm system. They stimulate angiogenesis and inflammatory reactions and facilitate cancer progression and invasion (4). Such HA fragments activate several cytoplasmic and extracellular signal transduction pathways associated with Raf-1 kinase, MAP kinase, and ERK. Short HA oligosaccharides are antiapoptotic and inducers of heat shock proteins. They regulate a different set of signaling molecules than the intermediate size HA including Erb2, PTEN phosphatase, and PI 3 kinase (4).Mammalian hyaluronidases are endo--N-acetyl-hexosaminidases (EC 3.2

The full repertoire of proteins that comprise the striated muscle Z-disc and peripheral structures, such as the costamere, have yet to be discovered. Recent studies suggest that this elaborate protein network, which acts as a structural and signaling center for striated muscle, harbors factors that function as mechanosensors to ensure coordinated contractile activity. Mutations in genes whose products reside in this region often result in skeletal and cardio myopathies, demonstrating the importance of this macromolecular complex in muscle structure and function. Here, we describe the characterization of a direct, downstream target gene for the MEF2A transcription factor encoding a large, muscle-specific protein that localizes to the costamere in striated muscle. This gene, called myospryn, was identified by microarray analysis as a transcript downregulated in MEF2A knock-out mice. MEF2A knock-out mice develop cardiac failure during the perinatal period with mutant hearts exhibiting several cardiac abnormalities including myofibrillar disarray. Myospryn is the mouse ortholog of a partial human cDNA of unknown function named cardiomyopathy-associated gene 5 (CMYA5). Myospryn is expressed as a single, large transcript of ϳ12 kilobases in adult heart and skeletal muscle with an open reading frame of 3739 amino acids. This protein, belonging to the tripartite motif superfamily of proteins, contains a B-box coiled-coil (BBC), two fibronectin type III (FN3) repeats, and SPRY domains and interacts with the sarcomeric Z-disc protein, ␣-actinin-2. Our findings demonstrate that myospryn functions directly downstream of MEF2A at the costamere in striated muscle potentially playing a role in myofibrillogenesis.