Crystal structure of an oligomer of proteolytic zymogens: detailed conformational analysis of the bovine ternary complex and implications for their activation 1 1Edited by I. A. Wilson

Gomis-Rüth, F.X.; Gomez-Ortiz, Mariola; Vendrell, Josep; Ventura, Salvador; Bode, Wolfram; Huber, Robert; Avilés, Francesc X.

doi:10.1006/jmbi.1997.1040

Cited by 28 publications

(17 citation statements)

References 71 publications

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“…The three-dimensional structure demonstrated that five disulfide bridges were formed at Cys1-Cys125 (according to the chymotrypsin numbering), Cys43-Cys59, Cys139-Cys206, Cys170-Cys186, and Cys196-Cys227 ( Figure 2B). CTRC (caldecrin) was shown to have a two-barrel structure, each composed of 6-7 β-sheets and a C-terminal α-helix long tail [14][15][16] ( Figure 2C). …”

Section: Activity Of Caldecrinmentioning

confidence: 99%

“…Osteoclast differentiation and maturation involves the following three steps: (1) Osteoclast precursor cells are generated from bone marrow cells in response to macrophage colonystimulating factor; (2) osteoclasts begin to differentiate from the precursor cells following stimulation by RANKL; and (3) at the later stage of differentiation, osteoclasts fuse to become multinucleated giant cells, leading to the cytoskeletal actin ring formation required for bone resorption. These processes are tightly regulated to well as elastase ⅡA, but not those of elastase Ⅰ, ⅢA, and ⅢB, where the pro-peptide is removed from the mature enzyme after tryptic activation [11,[14][15][16] . CTRC (caldecrin) is a serine protease with the characteristic charge-relayed catalytic triad (His58, Asp105, and Ser200), located in the active site cleft between the barrel structures [14][15][16] .…”

Section: Activity Of Caldecrinmentioning

confidence: 99%

“…These processes are tightly regulated to well as elastase ⅡA, but not those of elastase Ⅰ, ⅢA, and ⅢB, where the pro-peptide is removed from the mature enzyme after tryptic activation [11,[14][15][16] . CTRC (caldecrin) is a serine protease with the characteristic charge-relayed catalytic triad (His58, Asp105, and Ser200), located in the active site cleft between the barrel structures [14][15][16] . After tryptic activation, caldecrin changes its structure to a substrate-accessible catalytic cleft form.…”

Section: Activity Of Caldecrinmentioning

confidence: 99%

“…Therefore, the ELA4 PCR clone may be a cloning artifact or represent a mutant caldecrin gene. In 1995, the crystalline structure of bovine chymotrypsinogen C was reported [14][15][16] and its amino acid sequence was very close to that of rat caldecrin, thereby suggesting a similarity between caldecrin and chymotrypsin C (CTRC). It is now known that CTRC, caldecrin, and ELA4 are the same protein, which is encoded by the CTRC gene and known officially as CTRC (caldecrin), according to the HUGO Gene Nomenclature Committee.…”

Section: Introductionmentioning

confidence: 99%

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Caldecrin: A pancreas-derived hypocalcemic factor, regulates osteoclast formation and function

Tomomura

2015

WJBC

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Caldecrin was originally isolated from the pancreas as a factor that reduced serum calcium levels. This secreted serine protease has chymotrypsin-like activity and is also known as chymotrypsin C; it belongs to the elastase family. Although intravenous administration of caldecrin decreases the serum calcium concentration even when its protease activity is blocked, this effect does require cleavage of caldecrin's pro-peptide by trypsin, converting it to the mature enzyme. Ectopic intramuscular expression of caldecrin prevented bone resorption in ovariectomized mice. Caldecrin inhibited parathyroid hormone-stimulated calcium release from fetal mouse long bone organ cultures. Furthermore, caldecrin suppressed the formation of osteoclasts from bone marrow cells by inhibiting the receptor activator of nuclear factor-k B ligand (RANKL)-stimulated phospholipase Cγ-calcium oscillation-calcineurinnuclear factor of activated T-cells, cytoplasmic 1 pathway. Caldecrin also suppressed the bone resorption activity of mature osteoclasts by preventing RANKL-stimulated Src activation, calcium entry, and actin ring formation. In vivo and in vitro studies have indicated that caldecrin is a unique multifunctional protease with anti-osteoclastogenic activities that are distinct from its protease activity. Caldecrin might be a potential therapeutic target for the treatment of osteolytic diseases such as osteoporosis and osteoarthritis. This mini-review describes caldecrin's historical background and its mechanisms of action. Core tip: Caldecrin (also known as chymotrypsin C) reduces serum calcium levels. This activity is distinct from its protease activity but also requires trypsin-mediated cleavage of the pro-peptide, converting caldecrin to its active form. Ectopic intramuscular expression of caldecrin prevented bone resorption in ovariectomized mice. Caldecrin inhibited parathyroid hormone-stimulated calcium release from fetal mouse long bones. Furthermore, caldecrin suppressed receptor activator of nuclear factor- MINIREVIEWS

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Section: Activity Of Caldecrinmentioning

confidence: 99%

Section: Activity Of Caldecrinmentioning

confidence: 99%

Section: Activity Of Caldecrinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Caldecrin: A pancreas-derived hypocalcemic factor, regulates osteoclast formation and function

Tomomura

2015

WJBC

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“…The bovine ternary complex has been crystallized and its structure has been solved (39,40). In this complex chymotrypsinogen C and proproteinase E are bound to different surfaces of the centrally located proCPA.…”

mentioning

confidence: 99%

Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2

Szabó¹,

Pilsak

Bence³

et al. 2016

Journal of Biological Chemistry

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The pancreas secretes digestive proenzymes typically in their monomeric form. A notable exception is the ternary complex formed by proproteinase E, chymotrypsinogen C, and procarboxypeptidase A (proCPA) in cattle and other ruminants. In the human and pig pancreas binary complexes of proCPA with proelastases were found. To characterize complex formation among human pancreatic protease zymogens in a systematic manner, we performed binding experiments using recombinant proelastases CELA2A, CELA3A, and CELA3B; chymotrypsinogens CTRB1, CTRB2, CTRC, and CTRL1; and procarboxypeptidases CPA1, CPA2, and CPB1. We found that proCELA3B bound not only to proCPA1 (K D 43 nM) but even more tightly to proCPA2 (K D 18 nM), whereas proCELA2A bound weakly to proCPA1 only (K D 152 nM). Surprisingly, proCELA3A, which shares 92% identity with proCELA3B, did not form stable complexes due to the evolutionary replacement of Ala 241 with Gly. The polymorphic nature of position 241 in both CELA3A (ϳ4% Ala 241 alleles) and CELA3B (ϳ2% Gly 241 alleles) points to individual variations in complex formation. The functional effect of complex formation was delayed procarboxypeptidase activation due to increased affinity of the inhibitory activation peptide, whereas proelastase activation was unchanged. We conclude that complex formation among human pancreatic protease zymogens is limited to a subset of proelastases and procarboxypeptidases. Complex formation stabilizes the inhibitory activation peptide of procarboxypeptidases and thereby increases zymogen stability and controls activation.The exocrine pancreas produces digestive enzymes including serine-and metalloproteases secreted as inactive precursors (zymogens) that attain their active form in the duodenum. Physiological activation of protease zymogens is initiated by enteropeptidase-mediated activation of trypsinogen to trypsin followed by trypsin-mediated activation of chymotrypsinogens, proelastases, and procarboxypeptidases (1). Full activation of human procarboxypeptidases A1 (proCPA1) 2 and A2 (proCPA2) requires additional cleavages by chymotrypsin C (CTRC) to facilitate dissociation of the inhibitory activation peptide (2). Renewed interest in digestive protease physiology was spurred by the recognition that mutations in cationic trypsinogen (PRSS1), the pancreatic secretory trypsin inhibitor (SPINK1), CTRC and CPA1 are strongly associated with chronic pancreatitis in humans (3-6). At the same time, information obtained from genome and pancreatic transcriptome sequencing allowed correct annotation of the full complement of digestive protease isoforms and opened up avenues for investigations using genetically-defined recombinant enzymes. These studies, in turn, led to novel insight into digestive protease function such as the central role of CTRC in the regulation of human trypsinogen (7-9) and procarboxypeptidase activation (2), the role of mesotrypsin (PRSS3) in degrading trypsin inhibitors (10, 11), and the significance of mutation-induced digestive protease misfolding in acinar ce...

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Metallocarboxypeptidases

Vendrell¹,

Avilés²,

Fricker³

2004

Handbook of Metalloproteins

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Metallocarboxypeptidases (CP) catalyze the removal of C‐terminal amino acids from proteins and/or peptides. The different members of the CP family differ in their specificity for C‐terminal residues and physiological function and can be divided into two subfamilies. Members of the A/B subfamily are generally produced as proenzymes, contain an approximately 300‐residue CP catalytic domain, have greatest amino acid sequence identity to the exocrine pancreatic enzymes CPA and CPB, and prefer hydrophobic or basic residues. They function in the breakdown of peptides in food or in other physiological processes ranging from inflammation to fibrinolysis. Members of the N/E group cleave C‐terminal basic residues and are not produced as inactive proenzymes but contain an approximately 80‐residue region following the 300‐residue CP domain with structural homology to transthyretin. They act either extra‐ or intracellularly in the processing of peptide hormones and neurotransmitters and other physiologically relevant peptides. The tertiary folding of CPs corresponds to the α/β hydrolase fold and is formed by a central mixed parallel/antiparallel eight‐strand β‐sheet, with a 120° twist between the first and the last strand, over which eight α‐helices pack on both sides to form a globular molecule. All of the enzymatically active CPs bind one atom of Zn 2+ at the active site. Some members of the CP family that are inactive against standard CP substrates lack some of the cation‐binding ligands and may therefore not be able to bind the metal.

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Crystal structure of an oligomer of proteolytic zymogens: detailed conformational analysis of the bovine ternary complex and implications for their activation 1 1Edited by I. A. Wilson

Cited by 28 publications

References 71 publications

Caldecrin: A pancreas-derived hypocalcemic factor, regulates osteoclast formation and function

Caldecrin: A pancreas-derived hypocalcemic factor, regulates osteoclast formation and function

Complex Formation of Human Proelastases with Procarboxypeptidases A1 and A2

Metallocarboxypeptidases

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