Nucleic Acids Research, Vol 26, Issue 2 439-445, Copyright © 1998 by Oxford University Press
W Hassfeld, EKL Chan, DA Mathison, D Portman, G Dreyfuss, G Steiner and EM Tan
Serum from a patient showing symptoms related to autoimmunity was found to
contain autoantibodies to the nuclear mitotic apparatus (NuMA) protein and
to several novel nuclear antigens with estimated molecular weights of 40,
43, 72, 74 and 82 kDa. Using this serum for screening a human cDNA
expression library a 2.5 kb cDNA clone was isolated which encoded the
complete sequence of a protein of 633 amino acids. Sequence analysis
revealed a modular structure of the protein: an acidic N- terminal region
of approximately 150 amino acids was followed by three adjacent consensus
sequence RNA binding domains located in the central part of the protein. In
the C-terminal portion a nuclear localization signal and an octapeptide
(PPPRMPPP) with similarity to a major B cell epitope of the snRNP core
protein B were identified. This was followed by a glycine- and
arginine-rich section of approximately 120 amino acids forming another type
of RNA binding motif, a RGG box. Interestingly, three copies of a
tyrosine-rich decapeptide were found interspersed in the RGG box region.
The major in vitro translation product of the cDNA co-migrated in SDS-PAGE
with the 82 kDa polypeptide that was recognized by autoantibodies. The
structural motifs as well as the immunofluorescence pattern generated by
anti-82 kDa antibodies suggested that the antigen was one of the proteins
of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex.
Subsequently the 82 kDa antigen was identified as hnRNP R protein by its
presence in immunoprecipitated hnRNP complexes and co-migration of the
recombinant protein with this hitherto uncharacterized hnRNP constituent in
two- dimensional gel electrophoresis. The concomitant autoimmune response
to a hnRNP component of the pre-mRNA processing machinery and to NuMA, a
protein engaged in mitotic events and reported to be associated with mRNA
splicing complexes in interphase, may indicate physical and functional
association of these antigens. Support for this notion comes from
observations that concomitant or coupling of autoantibody responses to
proteins which are associated with each other as components of subcellular
particles are often found in autoimmune diseases.
ARTICLES
Molecular definition of heterogeneous nuclear ribonucleoprotein R (hnRNP R) using autoimmune antibody: immunological relationship with hnRNP P
W. M. Keck Autoimmune Disease Center and DNA Core Laboratory for Structural Analysis, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
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