Human pancreatic trypsinogens undergo post-translational sulfation on Tyr(154), catalysed by the Golgi-resident enzyme tyrosylprotein sulfotransferase 2. Sequence alignments suggest that the sulfation of Tyr(154) is facilitated by a unique sequence context which is characteristically found in primate trypsinogens. In the search for genetic variants that might alter this sulfation motif, we identified a single nucleotide polymorphism (c.457G > C) in the PRSS2 (serine protease 2, human anionic trypsinogen) gene, which changed Asp(153) to a histidine residue (p.D153H). The p.D153H variant is common in subjects of African origin, with a minor allele frequency of 9.2%, whereas it is absent in subjects of European descent. We demonstrate that Asp(151) is the main determinant of tyrosine sulfation in anionic trypsinogen, as both the natural p.D153H variation and the p.D153N mutation result in a complete loss of trypsinogen sulfation. In contrast, mutation of Asp(156) and Glu(157) only slightly decrease tyrosine sulfation, whereas mutation of Gly(151) and Pro(155) has no effect. With respect to the biological relevance of the p.D153H variant, we found that tyrosine sulfation had no significant effect on the activation of anionic trypsinogen or the catalytic activity and inhibitor sensitivity of anionic trypsin. Taken together with previous studies, the observations of the present study suggest that the primary role of trypsinogen sulfation in humans is to stimulate autoactivation of PRSS1 (serine protease 1, human cationic trypsinogen), whereas the sulfation of anionic trypsinogen is unimportant for normal digestive physiology. As a result, the p.D153H polymorphism which eliminates this modification could become widespread in a healthy population.
Ronai, Z., Witt, H., Rickards, O., Destro-Bisol, G., Bradbury, A., & Sahin-Toth, M. (2009). A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2). BIOCHEMICAL JOURNAL, 418(1), 155-161 [10.1042/BJ20081848].
|Tipologia:||Articolo su rivista|
|Citazione:||Ronai, Z., Witt, H., Rickards, O., Destro-Bisol, G., Bradbury, A., & Sahin-Toth, M. (2009). A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2). BIOCHEMICAL JOURNAL, 418(1), 155-161 [10.1042/BJ20081848].|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore BIO/08|
Settore BIO/18 - Genetica
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1042/BJ20081848|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2009|
|Titolo:||A common African polymorphism abolishes tyrosine sulfation of human anionic trypsinogen (PRSS2)|
|Autori:||Ronai, Z; Witt, H; Rickards, O; Destro-Bisol, G; Bradbury, ARM; Sahin-Toth, M|
|Appare nelle tipologie:||01 - Articolo su rivista|