The overall goal of this proposal is to determine the expression, functions and regulatory mechanism of a novel member of lysyl oxidase (LOX) family, lysyl oxidase-like 3 (LOXL3), and its alternative forms in the aorta. LOX is a key enzyme in maintaining the elasticity of connective tissue by cross-linking lysine residues in collagen and elastin in the extracellular matrix. Impaired LOX activity in several heritable and acquired disorders is associated with severe structural and functional abnormalities of cardiovascular tissues resulting in ischemic heart disease, myocardial infarction, and arterial aneurysms. In addition to the amine oxidase activity, diverse new functional roles have been recently assigned to this protein in extracellular, intracellular and intranuclear spaces. Moreover, the recent identification of several lysyl oxidase-like proteins, each showing significant homology to LOX in sequence and domain structure, suggests that some of the multiple functions of LOX may be derived from the lysyl oxidase-like proteins. LOXL3, the newest member of this family, contains the conserved domains of LOX, such as the copper-binding motif, the residues for lysyl tyrosyl-quinone and the cytokine receptor-like domain. Interestingly, LOXL3 also possesses four copies of SRCR domains known to be involved in protein-protein interactions. Moreover, we have detected several splice variants of LOXL3 from various human tissues, which contain the domains for amine oxidase activity but lacks the repeated SRCR domains, indicating complex mechanism(s) regulating expression and activity of LOXL3. Furthermore, the expression of LOXL3 is primarily confined to the adult aorta within cardiovascular tissues. These new findings suggest that LOXL3 may have a potential role as an aorta-specific amine oxidase and may also play novel function(s) possibly through the interactive SRCR domains. Defining the expression and functions of LOXL3 and its alternative forms should provide insight into the roles of this protein plays a in maintaining the integrity of aorta and, further, lead to understanding its contribution to the pathogenesis of cardiovascular disorders.
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