Increased Activation of Hereditary Pancreatitis-associated Human Cationic Trypsinogen Mutants in Presence of Chymotrypsin C

Szabó, András; Sahin–Tóth, Miklós

doi:10.1074/jbc.m112.360065

Cited by 86 publications

(148 citation statements)

References 34 publications

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“…Mutations in the best characterized risk genes PRSS1 (cationic trypsinogen), SPINK1 (pancreatic secretory trypsin inhibitor), and CTRC (chymotrypsin C) stimulate activation of trypsinogen and result in elevated trypsin activity in the pancreas [4][5][6][7][8][9]. More recently, loss-of-function variants in the CPA1 gene encoding carboxypeptidase A1 were shown to increase risk for early onset CP [10].…”

Section: Introductionmentioning

confidence: 99%

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

et al. 2017

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Human chymotrypsin-like elastases 3A and 3B (CELA3A and CELA3B) are the products of gene duplication and share 92% identity in their primary structure. CELA3B forms stable complexes with procarboxypeptidases A1 and A2 whereas CELA3A binds poorly due to the evolutionary substitution of Ala241 with Gly in exon 7. Since position 241 is polymorphic both in CELA3A (p.G241A) and CELA3B (p.A241G), genetic analysis can directly assess whether individual variability in complex formation might alter risk for chronic pancreatitis. Here we sequenced exon 7 of CELA3A and CELA3B in a cohort of 225 subjects with chronic pancreatitis (120 alcoholic and 105 non-alcoholic) and 300 controls of Hungarian origin. Allele frequencies were 2.5% for CELA3A p.G241A and 1.5% for CELA3B p.A241G in controls, and no significant difference was observed in patients. Additionally, we identified six synonymous variants, two missense variants, a gene conversion event and ten variants in the flanking intronic regions. Variant c.643-7G>T in CELA3B showed an association with alcoholic chronic pancreatitis with a small protective effect (OR = 0.59, 95% CI = 0.39-0.89, p = 0.01). Functional analysis of missense variants revealed no major defects in secretion or activity. We conclude that variants affecting amino-acid position 241 in CELA3A and CELA3B are not associated with chronic pancreatitis, indicating that changes in complex formation between proelastases and procarboxypeptidases do not alter pancreatitis risk.

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Section: Introductionmentioning

confidence: 99%

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

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“…Hereditary pancreatitis is an autosomal dominant disorder caused by mutations in PRSS1 that result in increased intra-pancreatic trypsinogen activation (8,9). The mutations alter cleavage of regulatory nick sites by chymotrypsin C (CTRC) 2 and trypsin that control trypsinogen degradation and autoactivation (10).…”

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“…CTRC-mediated degradation effectively curbs autoactivation of trypsinogen, resulting in diminished trypsin levels. Importantly, a single mutation of either Leu-81 or Arg-122 is enough to stabilize cationic trypsinogen and allow robust autoactivation even in the presence of CTRC (10).…”

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“…1A) (10,13). PRSS1 mutations associated with hereditary pancreatitis can decrease or eliminate cleavage at Leu-81 (N29I, N29T, V39A, R122C, and R122H) and Arg-122 (V39A, R122C, and R122H) or increase cleavage of the activation peptide at Phe-18 (A16V and N29I) (Fig.…”

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confidence: 99%

“…1A). As a result, cationic trypsinogen mutants autoactivate to high trypsin levels in the presence of CTRC (10).…”

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Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis

Jancsó

Sahin–Tóth

2016

Journal of Biological Chemistry

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The human pancreas expresses two major trypsinogen isoforms, cationic trypsinogen (PRSS1) and anionic trypsinogen (PRSS2). Mutations in PRSS1 cause hereditary pancreatitis by altering cleavage of regulatory nick sites by chymotrypsin C (CTRC) resulting in reduced trypsinogen degradation and increased autoactivation. Despite 90% identity with PRSS1 and a strong propensity for autoactivation, mutations in PRSS2 are not found in hereditary pancreatitis suggesting that activation of this isoform is more tightly regulated. Here, we demonstrated that CTRC promoted degradation and thereby markedly suppressed autoactivation of human anionic trypsinogen more effectively than previously observed with cationic trypsinogen. Increased sensitivity of anionic trypsinogen to CTRC-mediated degradation was due to an additional cleavage site at Leu-148 in the autolysis loop and the lack of the conserved Cys-139 -Cys-206 disulfide bond. Significant stabilization of anionic trypsinogen against degradation was achieved by simultaneous mutations of CTRC cleavage sites Leu-81 and Leu-148, autolytic cleavage site Arg-122, and restoration of the missing disulfide bridge. This stands in stark contrast to cationic trypsinogen where single mutations of either Leu-81 or Arg-122 resulted in almost complete resistance to CTRC-mediated degradation. Finally, processing of the trypsinogen activation peptide at Phe-18 by CTRC inhibited autoactivation of anionic trypsinogen, although cationic trypsinogen was strongly stimulated. Taken together, the observations indicate that human anionic trypsinogen is controlled by CTRC in a manner that individual natural mutations are unlikely to increase stability enough to promote intra-pancreatic activation. This unique biochemical property of anionic trypsinogen explains the lack of association of PRSS2 mutations with hereditary pancreatitis.

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History of chronic pancreatitis

Banks¹

2017

Pancreatitis

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Increased Activation of Hereditary Pancreatitis-associated Human Cationic Trypsinogen Mutants in Presence of Chymotrypsin C

Cited by 86 publications

References 34 publications

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

Genetic Analysis of Human Chymotrypsin-Like Elastases 3A and 3B (CELA3A and CELA3B) to Assess the Role of Complex Formation between Proelastases and Procarboxypeptidases in Chronic Pancreatitis

Tighter Control by Chymotrypsin C (CTRC) Explains Lack of Association between Human Anionic Trypsinogen and Hereditary Pancreatitis

History of chronic pancreatitis

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