Molecular basis of hereditary pancreatitis

Chen, Jian‐Min; Férec, Claude

doi:10.1038/sj.ejhg.5200492

Cited by 31 publications

(17 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…With the exception of human anionic Tg, which carries an Ile at position 21, all other mammalian Tgs sequenced to date contain Thr-21 (29). Recently, it has been proposed that the evolutionary divergence from Thr-21 found in other mammalian trypsins is the result of a positive selection process "endowing an as yet unknown advantageous effect" (30). The present observations provide tangible biochemical support for this theory.…”

Section: Discussionsupporting

confidence: 66%

Human Cationic Trypsinogen

Sahin–Tóth

2000

Journal of Biological Chemistry

139

View full text Add to dashboard Cite

Mutation Asn-21 3 Ile in human cationic trypsinogen (Tg-1) has been associated with hereditary pancreatitis. Recent studies with rat anionic Tg (Tg-2) indicated that the analogous Thr-21 3 Ile mutation stabilizes the zymogen against autoactivation, whereas it has no effect on catalytic properties or autolytic stability of trypsin (Sahin-Tó th, M. (1999) J. Biol. Chem. 274, 29699 -29704). In the present paper, human cationic Tg (Asn-21-Tg) and mutants Asn-21 3 Ile (Ile-21-Tg) and Asn-21 3 Thr (Thr-21-Tg) were expressed in Escherichia coli, and zymogen activation, zymogen degradation, and trypsin autolysis were studied. Enterokinase activated Asn-21-Tg approximately 2-fold better than Ile-21-Tg or Thr-21-Tg, and catalytic parameters of trypsins were comparable. At 37°C, in 5 mM Ca 2؉ , all three trypsins were highly stable. In the absence of Ca 2؉ , Asn-21-and Ile-21-trypsins suffered autolysis in an indistinguishable manner, whereas Thr-21-trypsin exhibited significantly increased stability. In sharp contrast to observations with the rat proenzyme, at pH 8.0, 37°C, autoactivation kinetics of Asn-21-Tg and Ile-21-Tg were identical; however, at pH 5.0, Ile-21-Tg autoactivated at an enhanced rate relative to Asn-21-Tg. Remarkably, at both pH values, Thr-21-Tg showed markedly higher autoactivation rates than the two other zymogens. Finally, autocatalytic proteolysis of human zymogens was limited to cleavage at Arg-117, and no digestion at Lys-188 was detected. The observations indicate that zymogen stabilization by Ile-21 as observed in rat Tg-2 is not characteristic of human Tg-1. Instead, an increased propensity to autoactivation under acidic conditions might be relevant to the pathomechanism of the Asn-21 3 Ile mutation in hereditary pancreatitis. In the same context, faster autoactivation and increased trypsin stability caused by the Asn-21 3 Thr mutation in human Tg-1 might provide a rationale for the evolutionary divergence from Thr-21 found in other mammalian trypsinogens. Hereditary pancreatitis (HP)1 is a relatively rare autosomal dominant disorder, characterized by early onset episodes of acute pancreatitis with frequent progression to chronic pancreatitis (1-4). Two mutations in the cationic trypsinogen (Tg) gene, Arg-117 3 His and Asn-21 3 Ile, have been identified in patients affected by HP worldwide (2-10). It has been proposed that mutation Arg-117 3 His eliminates a trypsin-sensitive cleavage site on trypsin and leads to pancreatitis by rendering prematurely activated trypsin resistant to inactivation through autolysis or proteolysis by trypsin-like enzymes (5). Degradation of trypsin by such mechanisms in the pancreas is believed to serve as a fail-safe mechanism against excessive trypsin accumulation (11-13). Although direct biochemical evidence with recombinant human cationic Tg is still lacking, Arg-117 has been shown to be a critical autolysis site in bovine (14) as well as rat (15) anionic trypsin, and mutations of this residue stabilize rat anionic trypsin against autolysis (16 -18). Arg-117 is...

show abstract

Section: Discussionsupporting

confidence: 66%

Human Cationic Trypsinogen

Sahin–Tóth

2000

Journal of Biological Chemistry

139

View full text Add to dashboard Cite

show abstract

“…The routinely used Afl-III restriction digestion assay for the PRSS1-R122H mutation does not detect this variant; therefore, DNA-sequencing is recommended to screen patients from hereditary pancreatitis families [Chen and Férec, 2000b;Howes et al, 2001]. The R122H double-nucleotide substitution variant was the first convincing example of a possible gene conversion event leading to a pancreatitis-causing trypsinogen mutation (see below).…”

Section: Arg122 In Prss1 Is a Mutational Hotspotmentioning

confidence: 99%

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

et al. 2006

View full text Add to dashboard Cite

“…The remaining protein is regarded as the mature protein, and the delivery of these proteins to the correct cellular location must be made accurately. Mistakes or mutation in the signal peptide cleavage position may result in the protein being delivered to the wrong cellular location and causing disease [2]. Almost 15% of human proteins contain SPs [3] and such proteins are either secreted or inserted into membranes as type I membrane proteins.…”

Section: Introductionmentioning

confidence: 99%

Signal peptide discrimination and cleavage site identification using SVM and NN

Kazemian

Yusuf

White

2014

Computers in Biology and Medicine

View full text Add to dashboard Cite

This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. a b s t r a c tAbout 15% of all proteins in a genome contain a signal peptide (SP) sequence, at the N-terminus, that targets the protein to intracellular secretory pathways. Once the protein is targeted correctly in the cell, the SP is cleaved, releasing the mature protein. Accurate prediction of the presence of these short aminoacid SP chains is crucial for modelling the topology of membrane proteins, since SP sequences can be confused with transmembrane domains due to similar composition of hydrophobic amino acids. This paper presents a cascaded Support Vector Machine (SVM)-Neural Network (NN) classification methodology for SP discrimination and cleavage site identification. The proposed method utilises a dual phase classification approach using SVM as a primary classifier to discriminate SP sequences from Non-SP. The methodology further employs NNs to predict the most suitable cleavage site candidates. In phase one, a SVM classification utilises hydrophobic propensities as a primary feature vector extraction using symmetric sliding window amino-acid sequence analysis for discrimination of SP and Non-SP. In phase two, a NN classification uses asymmetric sliding window sequence analysis for prediction of cleavage site identification.The proposed SVM-NN method was tested using Uni-Prot non-redundant datasets of eukaryotic and prokaryotic proteins with SP and Non-SP N-termini. Computer simulation results demonstrate an overall accuracy of 0.90 for SP and Non-SP discrimination based on Matthews Correlation Coefficient (MCC) tests using SVM. For SP cleavage site prediction, the overall accuracy is 91.5% based on cross-validation tests using the novel SVM-NN model.

show abstract

Molecular basis of hereditary pancreatitis

Cited by 31 publications

References 38 publications

Human Cationic Trypsinogen

Human Cationic Trypsinogen

Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis

Signal peptide discrimination and cleavage site identification using SVM and NN

Contact Info

Product

Resources

About