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Erythropoietin structure-function relationships: high degree of sequence
homology among mammals
D Wen, JP Boissel, TE Tracy, RH Gruninger, LS Mulcahy, J Czelusniak, M Goodman and HF Bunn
Hematology/Oncology Division, Brigham and Women's Hospital, Harvard Medical
School, Boston, MA 02115.
To investigate structure-function relationships of erythropoietin (Epo), we
have obtained cDNA sequences that encode the mature Epo protein of a
variety of mammals. A first set of primers, corresponding to conserved
nucleotide sequences between mouse and human DNAs, allowed us to amplify by
polymerase chain reaction (PCR) intron 1/exon 2 fragments from genomic DNA
of the hamster, cat, lion, dog, horse, sheep, dolphin, and pig. Sequencing
of these fragments permitted the design of a second generation of
species-specific primers. RNA was prepared from anemic kidneys and
reverse-transcribed. Using our battery of species-specific 5' primers, we
were able to successfully PCR- amplify Epo cDNA from Rhesus monkey, rat,
sheep, dog, cat, and pig. Deduced amino acid sequences of mature Epo
proteins from these animals, in combination with known sequences for human,
Cynomolgus monkey, and mouse, showed a high degree of homology, which
explains the biologic and immunological cross-reactivity that has been
observed in a number of species. Human Epo is 91% identical to monkey Epo,
85% to cat and dog Epo, and 80% to 82% to pig, sheep, mouse, and rat Epos.
There was full conservation of (1) the disulfide bridge linking the NH2 and
COOH termini; (2) N-glycosylation sites; and (3) predicted amphipathic
alpha- helices. In contrast, the short disulfide bridge (C29/C33 in humans)
is not invariant. Cys33 was replaced by a Pro in rodents. Most of the amino
acid replacements were conservative. The C-terminal part of the loop
between the C and D helices showed the most variation, with several amino
acid substitutions, deletions, and/or insertions. Calculations of maximum
parsimony for intron 1/exon 2 sequences as well as coding sequences enabled
the construction of cladograms that are in good agreement with known
phylogenetic relationships.
Volume 82,
Issue 5,
pp. 1507-1516,
09/01/1993
Copyright © 1993 by The American Society of Hematology
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