Post-poly(Glu) cleavage and degradation modified by O-sulfated tyrosine: a novel post-translational processing mechanism.
Expression of bioactive peptides requires several modifications of the primary translation product. Gastrin, a vertebrate gut hormone, occurs in multiple forms, including a bioactive fragment of the predominant gastrin-17. Gastrin-17 is, however, without known cleavage sites. In order to identify the new site, we therefore isolated, from antral mucosa, fragments of gastrin-34 and -17 monitored by monospecific immunoassays. After three steps of reverse-phase chromatography, the short gastrins were identified as hepta-, hexa- and pentapeptide amides. By far the most abundant of these was tyrosine O-sulfated gastrin-6. The near complete sulfation contrasts with the larger gastrins, of which only half are sulfated. The longest N-terminal fragment of gastrin-34 was a hexadecapeptide without complementarity to the short gastrins. Instead, the predominant N-terminal fragment of gastrin-17 was the decapeptide complementary to gastrin-7. Therefore the novel processing site is the Glu10-Ala11 bond that follows a poly(Glu6-10) sequence. Moreover, gastrin-7 is apparently trimmed, with subsequent accumulation of sulfated gastrin-6. Consequently, O-sulfated tyrosine ensures production of a new hormone which stimulates gastric acid secretion as potently as gastrin-17.
Rehfeld
J F
JF
Department of Clinical Biochemistry, University of Copenhagen, Denmark.
Hansen
C P
CP
Johnsen
A H
AH
D000577:Amides; D000595:Amino Acid Sequence; D000818:Animals; D005755:Gastrins / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011099:Polyglutamic Acid / Q000378:metabolism*; D011498:Protein Precursors / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013431:Sulfates / Q000378:metabolism; D013552:Swine; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism*
D000577:Amides; D005755:Gastrins; D011498:Protein Precursors; D013431:Sulfates; D011099:Polyglutamic Acid; C013706:big gastrin; D014443:Tyrosine