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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1440-1450
Proteolytic Processing of Big Endothelin-3 by the Kell Blood Group
Protein
Soohee Lee,
Melissa Lin,
Aldo Mele,
Ying Cao,
James Farmar,
David Russo, and
Colvin Redman
From The Lindsley F. Kimball Research Institute of the New York Blood
Center, New York, NY.
Kell blood group protein shares a consensus sequence (H.E.X.X.H)
with a large family of zinc-dependent endopeptidases. Kell has closest
homology with neutral endopeptidase 24.11, endothelin converting
enzyme-1 (ECE-1), and the PEX gene product that, as a group,
comprise the M13 subfamily of mammalian neutral endopeptidases. The
proteolytic activity of the M13 members, but not of Kell, has been
previously demonstrated. A secreted form of wild-type Kell protein
(s-Kell), devoid of the intracellular and transmembrane domains, was
expressed in sf9 cells. As a negative control, an inactive mutant Kell
protein (E582G) was expressed. As determined by N-terminal amino acid
sequencing and mass spectrometry of the cleaved products, wild-type
s-Kell, but not the control mutant protein, specifically cleaved big
endothelin-3 (ET-3) at Trp21-Ile22, yielding
ET-3, and, to a much lesser extent, also cleaved big ET-1 and big ET-2
at Trp21-Val22, yielding ET-1 and ET-2.
Enzymatic activity was partially inhibited by phosphoramidon. s-Kell
has an acidic pH optimum (pH 6.0 to 6.5). Like the recombinant protein,
red blood cells of common Kell phenotype also preferentially process
big ET-3, in contrast to Ko (null) cells that do not. These data
demonstrate that the Kell blood group protein is a proteolytic enzyme
that processes big ET-3, generating ET-3, a potent bioactive peptide
with multiple biological roles.
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