scholarly journals The protein structures that shape caspase activity, specificity, activation and inhibition

2004 ◽  
Vol 384 (2) ◽  
pp. 201-232 ◽  
Author(s):  
Pablo FUENTES-PRIOR ◽  
Guy S. SALVESEN
Keyword(s):  
Catalytic Mechanism ◽  
Protein Structures ◽  
Limited Proteolysis ◽  
Point Of View ◽  
Coagulation Cascade ◽  
Structural Basis ◽  
Apoptotic Pathway ◽  
Naturally Occurring ◽  
The Many ◽  
Apoptosis Regulation

The death morphology commonly known as apoptosis results from a post-translational pathway driven largely by specific limited proteolysis. In the last decade the structural basis for apoptosis regulation has moved from nothing to ‘quite good’, and we now know the fundamental structures of examples from the initiator phase, the pre-mitochondrial regulator phase, the executioner phase, inhibitors and their antagonists, and even the structures of some substrates. The field is as well advanced as the best known of proteolytic pathways, the coagulation cascade. Fundamentally new mechanisms in protease regulation have been disclosed. Structural evidence suggests that caspases have an unusual catalytic mechanism, and that they are activated by apparently unrelated events, depending on which position in the apoptotic pathway they occupy. Some naturally occurring caspase inhibitors have adopted classic inhibition strategies, but other have revealed completely novel mechanisms. All of the structural and mechanistic information can, and is, being applied to drive therapeutic strategies to combat overactivation of apoptosis in degenerative disease, and underactivation in neoplasia. We present a comprehensive review of the caspases, their regulators and inhibitors from a structural and mechanistic point of view, and with an aim to consolidate the many threads that define the rapid growth of this field.

Structures of c-di-GMP/cGAMP degrading phosphodiesterase VcEAL: identification of a novel conformational switch and its implication

2019 ◽  
Vol 476 (21) ◽  
pp. 3333-3353 ◽  
Author(s):  
Malti Yadav ◽  
Kamalendu Pal ◽  
Udayaditya Sen
Keyword(s):  
Active Site ◽  
Metal Binding ◽  
Metal Ion ◽  
Triosephosphate Isomerase ◽  
Catalytic Mechanism ◽  
Degradation Mechanism ◽  
Structural Basis ◽  
Conserved Residues ◽  
Phosphodiester Bond ◽  
Cyclic Dinucleotides

Cyclic dinucleotides (CDNs) have emerged as the central molecules that aid bacteria to adapt and thrive in changing environmental conditions. Therefore, tight regulation of intracellular CDN concentration by counteracting the action of dinucleotide cyclases and phosphodiesterases (PDEs) is critical. Here, we demonstrate that a putative stand-alone EAL domain PDE from Vibrio cholerae (VcEAL) is capable to degrade both the second messenger c-di-GMP and hybrid 3′3′-cyclic GMP–AMP (cGAMP). To unveil their degradation mechanism, we have determined high-resolution crystal structures of VcEAL with Ca2+, c-di-GMP-Ca2+, 5′-pGpG-Ca2+ and cGAMP-Ca2+, the latter provides the first structural basis of cGAMP hydrolysis. Structural studies reveal a typical triosephosphate isomerase barrel-fold with substrate c-di-GMP/cGAMP bound in an extended conformation. Highly conserved residues specifically bind the guanine base of c-di-GMP/cGAMP in the G2 site while the semi-conserved nature of residues at the G1 site could act as a specificity determinant. Two metal ions, co-ordinated with six stubbornly conserved residues and two non-bridging scissile phosphate oxygens of c-di-GMP/cGAMP, activate a water molecule for an in-line attack on the phosphodiester bond, supporting two-metal ion-based catalytic mechanism. PDE activity and biofilm assays of several prudently designed mutants collectively demonstrate that VcEAL active site is charge and size optimized. Intriguingly, in VcEAL-5′-pGpG-Ca2+ structure, β5–α5 loop adopts a novel conformation that along with conserved E131 creates a new metal-binding site. This novel conformation along with several subtle changes in the active site designate VcEAL-5′-pGpG-Ca2+ structure quite different from other 5′-pGpG bound structures reported earlier.

Public Investment Criteria: Benefit-Cost Analysis for Planned Economic Growth by Stephen A. Marglin. London: George Allen & Unwin Ltd., 1967. pp.103. 22s. 6d.********** Investments for Capacity Expansion: Size, Location and Time-Phasing edited by Alan S. Manne. London: George Allen & Unwin Ltd., 1967. pp.239. 45s.Investments for Capacity Expansion: Size, Location and Time-Phasing edited by Alan S. Manne. London: George Allen & Unwin Ltd., 1967. pp.239. 45s.

1967 ◽  
Vol 7 (3) ◽  
pp. 416-420
Author(s):  
Arthur MacEwan
Keyword(s):  
Cost Benefit Analysis ◽  
Public Investment ◽  
Cost Benefit ◽  
Capacity Expansion ◽  
Point Of View ◽  
Systematic Analysis ◽  
Benefit Cost Analysis ◽  
The Government ◽  
The Many ◽  
Benefit Cost

These books are numbers 4 and 5, respectively, in the series "Studies in the Economic Development of India". The two books are interesting complements to one another, both being concerned with the analysis of projects within national plan formulation. However, they treat different sorts of problems and do so on very different levels. Marglin's Public Investment Criteria is a short treatise on the problems of cost-benefit analysis in an Indian type economy, i.e., a mixed economy in which the government accepts a large planning responsibility. The book, which is wholely theoretical, explains the many criteria needed for evaluation of projects. The work is aimed at beginning students and government officials with some training in economics. It is a clear and interesting "introduction to the special branch of economics that concerns itself with systematic analysis of investment alternatives from the point of view of a government".

scholarly journals Grounding semantic transparency in context

Morphology ◽  
2021 ◽  
Author(s):  
Rossella Varvara ◽  
Gabriella Lapesa ◽  
Sebastian Padó
Keyword(s):  
Large Scale ◽  
Point Of View ◽  
Distributional Semantics ◽  
Semantic Transparency ◽  
Inclusion Measure ◽  
The Difference ◽  
Semantic Point ◽  
The Many ◽  
The Relationship

AbstractWe present the results of a large-scale corpus-based comparison of two German event nominalization patterns: deverbal nouns in -ung (e.g., die Evaluierung, ‘the evaluation’) and nominal infinitives (e.g., das Evaluieren, ‘the evaluating’). Among the many available event nominalization patterns for German, we selected these two because they are both highly productive and challenging from the semantic point of view. Both patterns are known to keep a tight relation with the event denoted by the base verb, but with different nuances. Our study targets a better understanding of the differences in their semantic import.The key notion of our comparison is that of semantic transparency, and we propose a usage-based characterization of the relationship between derived nominals and their bases. Using methods from distributional semantics, we bring to bear two concrete measures of transparency which highlight different nuances: the first one, cosine, detects nominalizations which are semantically similar to their bases; the second one, distributional inclusion, detects nominalizations which are used in a subset of the contexts of the base verb. We find that only the inclusion measure helps in characterizing the difference between the two types of nominalizations, in relation with the traditionally considered variable of relative frequency (Hay, 2001). Finally, the distributional analysis allows us to frame our comparison in the broader coordinates of the inflection vs. derivation cline.

scholarly journals Structural basis of Naa20 activity towards a canonical NatB substrate

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Dominik Layer ◽  
Jürgen Kopp ◽  
Miriam Fontanillo ◽  
Maja Köhn ◽  
Karine Lapouge ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Drug Development ◽  
Catalytic Mechanism ◽  
Peptide Binding ◽  
Competitive Inhibitor ◽  
Structural Basis ◽  
Substrate Affinity ◽  
Protein Homeostasis ◽  
Auxiliary Subunit

AbstractN-terminal acetylation is one of the most common protein modifications in eukaryotes and is carried out by N-terminal acetyltransferases (NATs). It plays important roles in protein homeostasis, localization, and interactions and is linked to various human diseases. NatB, one of the major co-translationally active NATs, is composed of the catalytic subunit Naa20 and the auxiliary subunit Naa25, and acetylates about 20% of the proteome. Here we show that NatB substrate specificity and catalytic mechanism are conserved among eukaryotes, and that Naa20 alone is able to acetylate NatB substrates in vitro. We show that Naa25 increases the Naa20 substrate affinity, and identify residues important for peptide binding and acetylation activity. We present the first Naa20 crystal structure in complex with the competitive inhibitor CoA-Ac-MDEL. Our findings demonstrate how Naa20 binds its substrates in the absence of Naa25 and support prospective endeavors to derive specific NAT inhibitors for drug development.

Heart failure in an elderly population

2001 ◽  
Vol 11 (4) ◽  
pp. 311-321
Author(s):  
DN Carmichael ◽  
Michael Lye
Keyword(s):  
Heart Failure ◽  
Treatment Options ◽  
Clinical Syndrome ◽  
Point Of View ◽  
Diagnostic Challenge ◽  
The Common ◽  
Characteristic Features ◽  
The Many ◽  
Neuroendocrine Activation ◽  
Symptoms And Signs

Heart failure has been defined in many ways and definitions change over time. The multiplicity of definitions reflect the paucity of our understanding of the primary underlying physiology of heart failure and the many diseases for which heart failure is the common end-point. Fundamentally, heart failure represents a failure of the heart to meet the body’s requirement for blood supply for whatever reason. It is thus a clinical syndrome with characteristic features – not a single disease in its own right. The syndrome includes symptoms and signs of organ underperfusion, fluid retention and neuroendocrine activation. The syndrome arises from a range of possible causes of which ischaemic heart disease is the commonest. From the point of view of a clinician, the underlying pathology will determine treatment options and prognosis. The extensive range of possible aetiologies present a diagnostic challenge both to correctly identify the syndrome amongst all other causes of dyspnoea and to identify the aetiology, allowing optimization of treatment.

THE CRITICALLY ILL CHILD: SICKLE CELL DISEASE CRISES AND THEIR MANAGEMENT

PEDIATRICS ◽  
1971 ◽  
Vol 48 (4) ◽  
pp. 629-635
Author(s):  
Howard A. Pearson ◽  
Louis K. Diamond
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Mutant Gene ◽  
Point Of View ◽  
Clinical Aspects ◽  
Cell Disease ◽  
Form And Function ◽  
Heterozygous Form ◽  
The Many ◽  
And Function

This brief review, being limited in scope to the recognition and management of the life-threatening and painful crises in infants and children with sickle-cell disease, has not even touched on the intriguing mystery of the molecular basis for the sickling phenomenon–how one amino-acid substitution (gene controlled) in the beta chain sequence of 146 amino acids can cause such serious disruption in form and function; or how this mutation occurred in the first place and why it has persisted in contrast to the rapid disappearance of many other deleterious mutants. Nor has there been even mention of the many milder symptoms, signs, and complications due to the presence of Hb. S., either in the homozygous (disease-producing) state or heterozygous form when found in combination with other hereditary hemoglobin defects. The accumulated knowledge about this mutant gene, its biochemical effects, and geographic distribution is enormous. From a fundamental scientific standpoint, sickle cell disease is one of the best understood of human afflictions. However, from a practical point of view treatment of the patient himself is often only symptomatic and palliative. Nevertheless, prompt and effective therapy of the myriad manifestations of sickle cell disease can effectively reduce morbidity and mortality. The pediatrician who cares for black children in his practice should be familiar with the cardinal diagnostic and clinical aspects of sickle cell disease and its crises.

THE ROAD AHEAD TO BETTER MEDICAL CARE FOR CHILDREN

PEDIATRICS ◽  
1950 ◽  
Vol 6 (3) ◽  
pp. 553-556
Keyword(s):  
Child Health ◽  
Medical Care ◽  
Medical Center ◽  
Point Of View ◽  
Medical Services ◽  
High Quality ◽  
The Road ◽  
Provide Child Care ◽  
Ultimate Objective ◽  
The Many

THE road to better child health has been discussed in relation to the doctor and his training, health services and their distribution. We have dealt with the unavoidable question of costs. Particular attention has been given to some of the advantages and dangers of decentralization of pediatric education and services. Each of the various subjects has been discussed from the point of view of its bearing on the ultimate objective of better health for all children and the steps necessary to attain this goal. Now, we may stand back from the many details of the picture, view the whole objectively and note its most outstanding features. First is the fact that the improvement of child health depends primarily upon better training for all doctors who provide child care, general practitioners as well as specialists. This is the foundation without which the rest of the structure cannot stand. The second dominant fact is the need for extending to outlying and isolated areas the high quality medical care of the medical centers, without at the same time diluting the service or training at the center. The road to better medical care, therefore, begins at the medical center and extends outward through a network of integrated community hospitals and health centers, finally reaching the remote and heretofore isolated areas. Inherent in all medical schools is a unique potential for rendering medical services as well as actually training physicians. The very nature of medical education—whereby doctors in training work under the tutelage of able specialists in the clinic, hospital ward, and out-patient department—provides medical services of high quality to people in the neighboring communities.

Polyculture de tilapia et Clarias en etang dans la commune de Pobè, sud-est du Benin.

2020 ◽  
Author(s):  
Kochikpa Ondodje
Keyword(s):  
Rural Areas ◽  
Eating Habits ◽  
National Level ◽  
Wholesale Price ◽  
Point Of View ◽  
Fish Farms ◽  
Technical Standards ◽  
Pipe System ◽  
The Many ◽  
Modern Breeding

Abstract The SARL "Pobè Fish Farm" located in the South-East of Benin specializes in the production and sale of tilapia and Clarias. The farm has twenty two ponds of 200 m2 (10 m × 20 m) supplied with water by a pipe system from a natural and permanent stream. The water supply is via a concrete channel which did not allow the water to be renewed once the pond is full. Work has been carried out to allow a larger inflow of water and communication between the ponds. The operation of the farm is modeled on the types of agro-fish farms existing in Asia and encountered in Vietnam in particular; it aims to put theoretical knowledge into practice and on the other hand to contribute to the development of a sector still little known in Benin, despite the many hydroagricultural potentials with which this country is endowed. The species bred at national level are rustic and adapted to the environment and whose genetic performance has not been improved. In fact, only modern breeding following very precise technical standards can allow obtaining interesting results from the point of view of agronomic yield and financial profitability. Indeed, these fish from our ponds are very popular with the populations (the average wholesale price is 1000 FCFA/kg) and are already an integral part of eating habits both in rural areas and in cities.

Exosite-dependent regulation of factor VIIIa by activated protein C

Blood ◽  
2003 ◽  
Vol 101 (12) ◽  
pp. 4802-4807 ◽  
Author(s):  
Chandrashekhara Manithody ◽  
Philip J. Fay ◽  
Alireza R. Rezaie
Keyword(s):  
Protein C ◽  
Time Course ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Limited Proteolysis ◽  
Activated Protein C ◽  
Coagulation Cascade ◽  
Factor Va ◽  
Factor Viiia

AbstractActivated protein C (APC) is a natural anticoagulant serine protease in plasma that down-regulates the coagulation cascade by degrading cofactors Va and VIIIa by limited proteolysis. Recent results have indicated that basic residues of 2 surface loops known as the 39-loop (Lys37-Lys39) and the Ca2+-binding 70-80–loop (Arg74 and Arg75) are critical for the anticoagulant function of APC. Kinetics of factor Va degradation by APC mutants in purified systems have demonstrated that basic residues of these loops are involved in determination of the cleavage specificity of the Arg506 scissile bond on the A2 domain of factor Va. In this study, we characterized the properties of the same exosite mutants of APC with respect to their ability to interact with factor VIIIa. Time course of the factor VIIIa degradation by APC mutants suggested that the same basic residues of APC are also critical for recognition and degradation of factor VIIIa. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) of the factor VIIIa cleavage reactions revealed that these residues are involved in determination of the specificity of both A1 and A2 subunits in factor VIIIa, thus facilitating the cleavages of both Arg336 and Arg562 scissile bonds in the cofactor.

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