Structure and evolutionary origin of the human granzyme H gene.
Among the molecules proposed to be involved in cytotoxic T lymphocyte (CTL), natural killer (NK) and lymphokine activated killer (LAK) cell-mediated lysis are the granzymes, a family of serine proteases stored in the cytoplasmic granules of CTLs, NK and LAK cells. In addition to the granzymes A and B, a third member of this family has been cloned in man and designated granzyme H. We present the complete gene sequence including the 5' promoter region and demonstrate that the granzyme H sequence represents a functional gene expressed in activated T cells. Granzyme H shows the highest degree (greater than 54%) of amino acid sequence homology with granzyme B and cathepsin G and, like these genes, consists of five exons separated by introns at equivalent positions. The evolutionary history of granzyme H has been analyzed by reconstructing an evolutionary tree for granzyme sequences. We provide evidence that interlocus recombination between the ancestral genes of granzyme B and granzyme H occurred about 21 million years ago, leading to a replacement of exon 3, intron 3 and part of exon 4 in human granzyme H by human granzyme B sequences. Our results suggest that the ancestral gene of granzyme H is more closely related to cathepsin G and granzyme B than to the murine granzymes C to G. Thus, granzyme H does not represent a human counterpart of the known murine granzymes A to G. It diverged from cathepsin G before mammalian radiation and should, therefore, exist in other mammalian lineages as well.
Haddad
P
P
Unité 93 INSERM, Paris, France.
Jenne
D
D
Tschopp
J
J
Clément
M V
MV
Mathieu-Mahul
D
D
Sasportes
M
M
D000595:Amino Acid Sequence; D001483:Base Sequence; D005075:Biological Evolution; D056649:Cathepsin G; D002403:Cathepsins / Q000235:genetics; D004247:DNA / Q000235:genetics; D015870:Gene Expression; D053804:Granzymes; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008969:Molecular Sequence Data; D015183:Restriction Mapping; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases / Q000235:genetics*
D004247:DNA; D002403:Cathepsins; C509213:GZMB protein, human; C069434:GZMH protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G