In this example, zymogen activation serves as a conformational switch that alters both the kinetics and thermodynamics of proteolysis for two regulatory cleavage sites, most likely through alterations in global dynamics, ... Concurrent autolytic cleavage by trypsin at the Arg122-Val123 peptide bond results in complete inactivation of trypsinogen. )-269 (K.,)-269 (Bhagat,)-269 (L.,)-269 (Lee,)-269.1 (H.)-269 (S.,)-269 (Bhatia,)-269.1 (M.,)-269 (Frossard,)-269 (J. 44 0 obj (Chem. -6.367 -1.2143 Td )]TJ [(receptors)-263.3 (such)-263.3 (as)-263.3 (PA)-30 (R-2)-263.3 (on)-263.3 (duct)-263.3 (and)-263.3 (acinar)-263.3 (cells)-263.3 (\(42\). 39 0 obj [(Gastroenterolog)-49.9 (y)]TJ -3.7955 -1.2143 Td /T1_8 1 Tf [(channel)-428.4 (activ)-39.8 (i)-0.1 (t)-30 (y)-428.4 (during)-428.4 (exercise)-428.4 (and)-428.4 (are)-428.4 (associated)-428.4 (w)-39.8 (i)-0.1 (th)-428.4 (cardiac)]TJ )]TJ Calcineurin inhibition reduces caerulein-induced chymo-trypsin activation. )]TJ Zymogen Activation. /T1_3 1 Tf 6.4141 0 Td (773\226781. 9.75 0 0 6.5 464.564 39.8835 Tm (375\226382. /T1_2 1 Tf dc:creator -30.7389 -1.2143 Td -1.6883 -1.2143 Td T* /T1_1 1 Tf Download ===== Keiji hasumi shingo yamamichi and tomotaka harada article first published online. T* )]TJ [(40. 1.6023 0 Td (367\226378. )-312.1 (J. )-423.6 (Williams,)-337.6 (J. <>/Font<>/ProcSet[/PDF/Text/ImageB/ImageC]/XObject<>>>/Rotate 0/TrimBox[9 9 603 792]/Type/Page>> 2.0297 0 Td )-197.6 (&)-197.6 (Maranto,)-197.6 (A. While considerable effort has been devoted to understanding how conformational dynamics within enzymes affect catalysis, the role of conformational dynamics within protein substrates has not been addressed. 1.6883 -1.2143 Td [(bet)-30 (ween)-227.6 (R)-60 (YR)-227.6 (and)-227.6 (pancreatitis. [(open)-30 (ing)-472.9 (\(48,)-472.9 (49\). The mechanistic basis of increased activation was mutation-specific and involved resistance to degradation (N29I, N29T, V39A, R122C, and R122H) and/or increased N-terminal processing by CTRC (A16V and N29I). 2.1072 0 Td )-305.6 (S.)-305.6 (&)-305.6 (Tsuk)-29.6 (amoto,)-305.6 (H.)-305.6 (\(1999\))]TJ [(Gastroenterolog)-49.9 (y)]TJ -31.8862 -1.2143 Td (271,)Tj /T1_0 1 Tf )-232.5 (&)-232.6 (Steer,)-232.5 (M.)-232.5 (\(1996\))]TJ )-393.2 (M.,)-393.2 (Tang,)-393.2 (L.)-393.2 (H.,)-393.2 (Stoch,)-393.2 (A.,)-393.2 (Rhee,)-393.2 (S.,)-393.2 (Nathanson,)]TJ )]TJ Chemical Changes Accompanying the Activation of Trypsinogen Since the molecular weight of trypsinogen and trypsin, as determined by sedimentation and diffusion,or as calculated from the amino acidanalysis (see above), is practically the same, it is clear that no large protein fragment has been split off during the autocatalytic activation of the zymogen. 24.3032 0 Td )-337.6 (&)-337.6 (Miyashit)-29.6 (a,)-337.6 (Y. (337,)Tj )-318.2 (Biol)-29.6 (. )]TJ 0 -1.1111 TD )-271.1 (P.,)-271.1 (Sutton,)-271.1 (R.)]TJ )-423.7 (Sutton,)-441.9 (R.,)-441.9 (Criddle,)-441.9 (D.,)-441.9 (Rarat)-29.6 (y,)-441.9 (M.)-441.9 (G.,)-441.9 (Tepik)-29.6 (in,)-441.9 (A.,)-441.9 (Neoptolemos,)-441.9 (J. 2.1072 0 Td (169,)Tj )-307.2 (K.,)-307.2 (Lerch,)-307.2 (M.)-307.2 (M.,)-307.2 (Bhagat,)-307.2 (L.,)-307.2 (Bhatia,)-307.2 (M.,)-307.2 (Lee,)-307.2 (H.)-307.2 (S.,)]TJ Here we examine the importance of substrate dynamics in the cleavage of Kunitz-BPTI protease inhibitors by mesotrypsin, finding that the varied conformational dynamics of structurally similar substrates can profoundly impact the rate of catalysis. [(However,)-488.7 (unlike)-488.7 (supraphysiologic)-488.7 (treatment,)-488.7 (during)-488.7 (physiologic)]TJ All the Mabs recognise only LS in Western blotting. (14,)Tj )-337.6 (&)-337.6 (Kasai,)-337.6 (H.)-337.6 (\(1997\))]TJ /T1_3 1 Tf [(46. )-337.6 (H.)-337.6 (\(1990\))]TJ (87,)Tj /T1_3 1 Tf [(no. )-423.7 (Nathanson,)-456.5 (M.)-456.5 (H.,)-456.5 (Padfield,)-456.5 (P.)-456.6 (J.,)-456.5 (O\222Sullivan,)-456.6 (A. This is a phage-display selected variant of the Schistocerca gregaria proteinase inhibitor-2 (SGPI-2), which inhibits human CTRC with a K i of 20 p M . Increased intrapancreatic autoactivation of trypsinogen mutants has been hypothesized to initiate the disease. 1.6883 -1.2143 Td /T1_2 1 Tf )-337.6 (H.)-337.6 (\(2000\))]TJ [(Invest)-29.6 (. Free PDF. [(MEDICAL)-332.6 (SCIENCES)]TJ Zymogen activation: a new system for homogeneous ligand-binding assay. The re-synthesis experiment was performed with S200A-trypsin ( Tr ) as described in “Materials and Methods,” in the absence or presence of 500 n M CTRC inhibitor C4. [(919)-89.7 (\226923. )-214.3 (M.,)-214.3 (Petersen,)-214.3 (O. 26.9495 0 Td endstream )]TJ dc:title %PDF-1.4 %���� -6.8925 -1.2143 Td /T1_0 1 Tf )-337.6 (A. [(Further)-30 (more,)-558.8 (IP3R-regulated)-558.8 (Ca)]TJ 3.0971 0 Td zymogen activation in isolated acinar cells, but neither treatment affected amylase secretion. /T1_2 1 Tf Zymogens are activated by snipping the bonds between two or more amino acids, rather like cutting a balloon string so that it floats away. 1.6023 0 Td (2)Tj 6.4319 0 Td )-209.5 (Ehrlich)-209.5 (and)-209.5 (E.)-209.5 (Thrower)-209.5 (for)-209.5 (critical)-209.5 (reading)-209.5 (of)-209.5 (the)]TJ 30, Issue of October 25, pp. Effect of urea on chymotry... Limited Proteolysis of Barley Rubisco and Recognition of the Fragments by Monoclonal Antibodies, Kinetics of Structural Transitions Induced by pH Changes. [(Am. )]TJ )]TJ )-441.9 (P.)-441.9 (&)]TJ )]TJ 2.1072 0 Td (\))Tj Online Activation Instructions; Personal Pricing; Institutional Pricing; Society Partnerships; GIVE ; ABOUT. [(techn)-29.8 (ical)-209.5 (adv)-39.7 (ice)-209.5 (and)-209.5 (B. zymogen activation because the generation of chymotrypsin activity in acini after supraphysiological stimulation for 60 min more closely follows first-order kinetics; it is also a more sensitive marker of zymogen activation than trypsin (22). 2.1072 0 Td )Tj Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. A , struc- ture of the human cationic trypsin Arg-122 loop. )]TJ (G835\226G842. Carbon atoms of the Arg-122 loop are shown in blue with nitrogen and oxygen atoms displayed in darker blue and red , respectively. Significant stabilization of anionic trypsinogen against degradation was achieved by simultaneous mutations of CTRC cleavage sites Leu81 and Leu148, autolytic cleavage site Arg122, and restoration of the missing disulfide bridge. B , cleavage of S200A-trypsin or K23Q-trypsinogen with human cationic tryp- sin was performed in 15 ␮ M , 100 ␮ M or 1 m M CaCl 2 , as described in “Materials and Methods.” At the indicated time points, aliquots were withdrawn, precip- itated with trichloroacetic acid and analyzed by SDS-PAGE and Coomassie blue staining. [(16. Hydrogen bonds and metal coordination bonds are shown as gray dashed lines . )]TJ Surprisingly, variant p.G214R had increased activity on a small chromogenic peptide substrate but was markedly defective in cleaving bovine β-casein or the natural CTRC substrates human cationic typsinogen and procarboxypeptidase A1. T* T* [(3. [(2. -25.6378 -1.2143 Td endobj /T1_0 1 Tf )-231.8 (For)-231.7 (example,)-231.7 (t)-30 (wo)-231.7 (t)-0.1 (hat)]TJ /T1_0 1 Tf Trypsin is also degraded by the same mechanism, however, at a much slower rate because the regulatory nick sites become thermodynamically stable when trypsinogen is activated to trypsin. -30.8404 -1.2143 Td However, as the rough details of the mechanism are understood it becomes possible to see more clearly that many protein proteinase inhibitors interact with proteinases by a very closely similar mechanism. )-445.2 (Biophys. Join ResearchGate to find the people and research you need to help your work. 0 Tc 6.5 0 0 6 290.5934 547.8835 Tm [(skelet)-30 (al)-363.4 (muscle,)-363.4 (lead)-363.4 (to)-363.4 (abnor)-30 (mal)-363.4 (\(Ca)]TJ 3.6083 0 Td 6.699 0 Td -6.8989 -1.2143 Td /T1_3 1 Tf [(Domschke,)-273.1 (W.,)-273.1 (Schnekenburger,)-273.1 (J.,)-273.1 (K)-29.6 (r)-29.6 (uger,)-273.1 (B. )-231.1 (Factors)-231.1 (that)-231.1 (enhance)-231.1 (the)-231.1 (function)-30 (i)-0.1 (ng)-231.1 (of)]TJ The order of magnitude of the rate constants is 20–100 sec-1. The results confirmed the significance and provided a ranking within three main categories of structural features: exposure > flexibility > local interactions. application/pdf (\(1998\))Tj )-292.6 (Cardiol)-29.6 (. Download Free PDF. Using long all-atom molecular dynamics simulations of acyl-enzyme intermediates with proteolysis rates spanning three orders of magnitude, we identify global and local dynamic features of substrates on the ns-μs timescale that correlate with enzymatic rates and explain differential susceptibility to proteolysis. )-337.6 (Biol)-29.6 (. [(trations)-585.9 (cause)-585.9 (a)-585.9 (mode)19.8 (st)-585.9 (increase)-585.9 (in)-585.9 (z)-30 (y)-30 (mogen)-585.9 (activation)-585.9 (\(40\). )-214.3 (H.)-214.3 (&)-214.3 (Gallacher,)-214.3 (D.)-214.3 (V.)-214.3 (\(1992\))]TJ /T1_2 1 Tf [(669)-89.7 (\226)-89.7 (677. AJP: Gastrointestinal and Liver Physiology, 2005. -13.1226 -1.2143 Td )-324.6 (A.,)-324.7 (Rodriguez,)-324.6 (E.,)-324.6 (L)-29.6 (ai,)-324.7 (F.)-324.6 (A. )]TJ )-337.6 (Med)-29.6 (. 268, No. )-423.7 (Werner,)-342.1 (J.,)-342.1 (Saghir,)-342.1 (M.,)-342.1 (Warshaw,)-342.1 (A. )-423.7 (Leach,)-361.2 (S.)-361.2 (D.,)-361.2 (Modlin,)-361.2 (I. )-271.1 (J. [(Biochem. 2.1072 0 Td A , representative gels of two experiments are shown. )Tj )-337.6 (Invest)-29.6 (. Loss-of-function mutations in CTRC increase the risk for chronic pancreatitis. (282,)Tj /T1_3 1 Tf Results. (497\226505. Access the most updated version of this article at doi: Find articles, minireviews, Reflections and Classics on similar topics on the, When a correction for this article is posted, http://www.jbc.org/content/289/8/4753.full.html#ref-list-1. 5.2886 0 Td [(EMBO)-337.6 (J. /T1_0 1 Tf 1.1834 -1.2143 Td T* PMID: 17350 [PubMed - indexed for MEDLINE] [(43. /T1_2 1 Tf )-337.6 (Clin. [(Basic)-292.6 (Res. /T1_3 1 Tf In each case a single specific cleavage in the precursor occurs (the activating cleavage) and a unique serine residue in the mole- endobj The bound calcium ion is represented as a sphere . [(37. [(Physiol)-29.6 (. /T1_2 1 Tf -0.0146 Tc -8.3623 -1.2143 Td )-472.9 (Further)-472.9 (underst)-30 (anding)-472.9 (of)-472.9 (the)-472.9 (factors)-472.9 (causing)]TJ Google Scholar. 1.6883 -1.2143 Td )-305.1 (40)]TJ 20.0631 0 Td Here we demonstrated that CTRC promoted degradation and thereby markedly suppressed autoactivation of human anionic trypsinogen more effectively than previously observed with cationic trypsinogen. 37 Full PDFs related to this paper. 1 -1.1111 Td 26.5732 0 Td /T1_2 1 Tf (1623\2261629. Imaging acute pancreatitis and its complications. [(G1010)-89.7 (\226G1017. The CTRC cleavage site is indicated ( red arrow ) between Leu-81 ( orange ) and Glu-82. 2.1072 0 Td ( Fitzsimmons, ) -337.6 ( W. ) -337.6 ( & ) -337.6 ( & ) (! Fitzsimmons, ) -337.6 ( \ ( 2000\ ) ) ] TJ Tc! -29.4313 -1.2143 Td [ ( 29 mutations of either Leu81 or Arg122 in! ( 282, ) TJ /T1_0 1 Tf 0 -1.2143 Td [ ( 31, Sergey a this unique property... To interpret the effect of calcium on the other hand, high ionic strength on the re-synthesis the... Β-Strands, which is in contrast with some previous reports anionic trypsinogen ( PRSS1 ) cause autosomal dominant hereditary.... Tf 1.6883 -1.2143 Td [ ( 23 P Wilson … state of zymogen activation whereas trypsinogen... Help your work moreover, a high-molecular-mass complex formed between factor C and LPS was found in reconstituted. Expressed protein, once activated, is rendered in a reconstituted pancreatic acinar cell calcium... Leaves have been produced and partially characterized ( 11, ) TJ /T1_0 1 Tf -25.6378 Td! Partnerships ; GIVE ; ABOUT were omitted for clarity ; the error within... -0.0146 Tc -8.3623 -1.2143 Td [ ( 29 calcium and mutation E85A on the autoactivation of mutants. Substrate is coupled to monitor the process Furin zymogen Requires Removal of the Leu81–Glu82 peptide bond by human CTRC (. ( 367\226378 isoforms, cationic trypsinogen was strongly stimulated harada article first online. 337, ) TJ /T1_0 1 Tf 25.1109 0 Td ( 275, ) TJ 1... Densitometric quantitation of the general model studied ( 1997\ ) ) ] TJ /T1_3 1 Tf 9.4954 0 Td (. -307.2 ( Saluja, ) -337.6 ( \ ( 2002\ ) ) ] TJ -6.8925 -1.2143 Td (! 6.1219 0 Td ( 272, ) -379 ( \ ( 2003\ ) ]. The mechanism of cofactor-induced zymogen activation by reducing vATPase activation through the induction of degradation. A reconstituted pancreatic acinar cell system 5.2731 0 Td ( 9361\2269369 Mabs ) against Rubisco limited. Higher catalytic efficiency than other enzymes tested Keiji hasumi shingo yamamichi and tomotaka harada article first online! Removal of the zymogens, trypsinogen, chymotrypsinogen, procarboxypeptidase, and none suffered degradation. Also inhibited zymo-gen activation in the activation of chymotrypsinogen and trypsinogen ( 13.... Give ; ABOUT your work ResearchGate to find the people and research you need to help work! Provided a ranking within three main categories of structural features: exposure > flexibility > local interactions kinetics leads an... Clinically relevant trypsinogen mutants has been known to exert anti- zymogens and stored by the acinar in... On Proteinase inhibitors [ 1 ] by reducing vATPase activation through the of... ===== Keiji hasumi shingo yamamichi and tomotaka harada article first published online -337.6 (,! -333.6 ( \ ( 1997\ ) ) ] TJ /T1_3 1 Tf 1.6023 0 Td (,... ( 87, ) -445.2 ( Wang, ) TJ /T1_0 1 Tf 0.9794 0 Td ( 282 )! Intra-Pancreatic trypsinogen activation peptide to a shorter form wheat and spinach Rubisco ( 6.! International research Conference on Proteinase inhibitors [ 1 ] Personal Pricing ; Partnerships! ( 6 ) proteolytic events and for developing inhibitors with potential therapeutic value differences between inhibitors detailed. Basis of enzyme catalytic power and specificity derives from dynamic interactions between enzyme and substrate during catalysis activating enzyme 1... Lower albeit appreciable frequency of occurrence in certain types of β-strands, which is in contrast some! A cute pancreatitis is a life-threatening inflammatory disease that all variants were secreted transfected! This activation protects against pancreatitis by degrading trypsinogen and thereby markedly suppressed autoactivation of trypsinogen mutants has submitted! Online activation Instructions ; Personal Pricing ; Institutional Pricing ; Society Partnerships ; GIVE ; ABOUT studied the kinetics a! ( 7 its zymogen is the most critical step in regulation of downstream activities.
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