Abstract
Goodpasture disease is an autoimmune disorder that occurs naturally only in humans. Also exclusive to humans is the phosphorylation process that targets the unique N-terminal region of the Goodpasture antigen. Here we report the molecular cloning of GPBP (Goodpasture antigen-binding protein), a previously unknown 624-residue polypeptide. Although the predicted sequence does not meet the conventional structural requirements for a protein kinase, its recombinant counterpart specifically binds to and phosphorylates the exclusive N-terminal region of the human Goodpasture antigen in vitro. This novel kinase is widely expressed in human tissues but shows preferential expression in the histological structures that are targets of common autoimmune responses. The work presented in this report highlights a novel gene to be explored in human autoimmunity.
Highlights
Goodpasture (GP)1 disease is an autoimmune disorder described only in humans
Recent studies indicate that the phosphorylation of the N terminus of the GP antigen by cAMP-dependent protein kinase is up-regulated by the presence of the alternative products
Our data show that GPBP is a novel non-conventional serine/ threonine kinase and present evidence that indicate that GPBP discriminates between human and bovine GP antigens and targets the exclusive human phosphorylatable region in vitro
Summary
Goodpasture (GP) disease is an autoimmune disorder described only in humans. In GP patients autoantibodies against the non-collagenous C-terminal domain (NC1) of the ␣3 chain of collagen IV cause a rapidly progressive glomerulonephritis and often lung hemorrhage, the two cardinal clinical manifestations of the GP syndrome (see Ref. 1 for review). Since the NC1 domain is a highly conserved domain among species and between the different collagen IV ␣ chains (␣1–␣6) (2), the exclusive involvement of the human ␣3(IV)NC1 in a natural autoimmune response suggests that this domain has structural and/or biological peculiarities of pathogenic relevance. Recent studies indicate that the phosphorylation of the N terminus of the GP antigen by cAMP-dependent protein kinase is up-regulated by the presence of the alternative products.. Specific serine/ threonine phosphorylation appears to be a major biological difference between the human antigen, antigen from other species, and the homologous domains from other human ␣(IV) chains and might be important in pathogenesis (1, 4). We report the cloning and characterization of a novel type of serine/threonine kinase that binds to and phosphorylates the unique N-terminal region of the human GP antigen
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