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PubMed1990

Conformational and helicoidal analysis of the molecular dynamics of proteins: "curves," dials and windows for a 50 psec dynamic trajectory of BPTI.

A new procedure for the graphic analysis of molecular dynamics (MD) simulations on proteins is introduced, in which comprehensive visualization of results and pattern recognition is greatly facilitated. The method involves determining the conformational and helicoidal parameters for each structure entering the analysis via the method "Curves," developed for proteins by Sklenar, Etchebest, and Lavery (Proteins: Structure, Function Genet. 6:46-60, 1989) followed by a novel computer graphic display of the results. The graphic display is organized systematically using conformation wheels ("dials") for each torsional parameter and "windows" on the range values assumed by the linear and angular helicoidal parameters, and is present in a form isomorphous with the primary structure per se. The complete time evolution of dynamic structure can then be depicted in a set of four composite figures. Dynamic aspects of secondary and tertiary structure are also provided. The procedure is illustrated with an analysis of a 50 psec in vacuo simulation on the 58 residue protein, bovine pancreatic trypsin inhibitor (BPTI), in the vicinity of the local minimum on the energy surface corresponding to a high resolution crystal structure. The time evolution of 272 conformational and 788 helicoidal parameters for BPTI is analyzed. A number of interesting features can be discerned in the analysis, including the dynamic range of conformational and helicoidal motions, the dynamic extent of 2 degrees structure motifs, and the calculated fluctuations in the helix axis. This approach is expected to be useful for a critical analysis of the effects of various assumptions about force field parameters, truncation of potentials, solvation, and electrostatic effects, and can thus contribute to the development of more reliable simulation protocols for proteins. Extensions of the analysis to present differential changes in conformational and helicoidal parameters is expected to be valuable in MD studies of protein complexes with substrates, inhibitors, and effectors and in determining the nature of structural changes in protein-protein interactions.

Biological Evolution↗
PubMed1992

Isoforms of the alpha subunit of Na,K-ATPase and their significance.

Recent studies of the Na,K-ATPase have demonstrated that multiple isoforms of both the alpha and beta subunits exist and that these are expressed in a tissue and developmental specific manner. In the case of the alpha subunit, there are three known isoforms, alpha 1, alpha 2 and alpha 3. We have examined adult human heart for the presence of these isoforms and found that all three exist in approximately equal amounts. This is in contrast to the adult rat heart which contains only alpha 1 and alpha 2 isoforms. The difference in abundance of various isoforms in various tissues could result from the necessity to express Na,K-ATPase with different properties at various developmental stages or in specific cell types. For example, enzymes with differences in Na+ or K+ affinity or the ability to respond to various effector molecules may be required. Alternatively, the presence of three isoforms may simply result from the triplication of the alpha subunit gene and the divergence of expression of these genes during evolution. In this case the isozymes would not confer a specific function to the Na,K-ATPase. In order to provide information with respect to these two alternatives, cell lines producing rat alpha 1, alpha 2 and alpha 3 were developed and the enzymatic properties of the resulting enzyme determined. The results indicate that Na,K-ATPase carrying the alpha 1 are alpha 2 isoforms are fairly similar while enzyme with the alpha 3 isoform differs in its apparent affinity for sodium. The K0.5 for Na+ is approximately three fold lower for this isoform.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The ras oncogenes.

Oncogenic forms of the p21ras genes have been found in a large variety of human malignancies and tumours induced in animals by chemical carcinogens or irradiation. The active form of the p21 ras proteins is the GTP bound state and oncogenic mutations result in the protein being constitutively in the GTP bound active state. There is evidence to suggest that activating mutations can occur either as initiating steps in carcinogenesis or as later events in the evolution to frank neoplasia. To transduce a signal for proliferation and transformation the active GTP form of p21ras must interact with one or more cellular targets. Genetic experiments suggest that one potential effector molecule is the GTPase activating protein GAP. However, the mechanism by which interaction with GAP results in proliferation and transformation remains to be elucidated.

Animals↗
PubMed1992

A family of bacterial regulators homologous to Gal and Lac repressors.

We describe a family of proteins which regulate transcription of inducible genes in bacteria (GalR-LacI family). An alignment of the proteins in the GalR-LacI family is presented in which these proteins show a very high degree of similarity (60%) throughout the entire sequences. The homology is greatest among the amino-terminal DNA binding domains. Since a portion of the operator sequences occupied by these proteins is also conserved, a similar DNA structure may be required for specific recognition of DNA by members of the GalR-LacI family. Highly conserved motifs involved in effector binding and oligomerization are also identified. This compilation suggests a widespread conservation of these regulators among bacteria, and have strong implications for further study of peptide motifs in domain function, as well as pathways of protein evolution.

Amino Acid Sequence↗
PubMed1991

Evolutionary aspects of cytochrome c oxidase.

The presence of additional subunits in cytochrome oxidase distinguish the multicellular eukaryotic enzyme from that of a simple unicellular bacterial enzyme. The number of these additional subunits increases with increasing evolutionary stage of the organism. Subunits I-III of the eukaryotic enzyme are related to the three bacterial subunits, and they are encoded on mitochondrial DNA. The additional subunits are nuclear encoded. Experimental evidences are presented here to indicate that the lower enzymatic activity of the mammalian enzyme is due to the presence of nuclear-coded subunits. Dissociation of some of the nuclear-coded subunits (e.g. VIa) by laurylmaltoside and anions increased the activity of the rat liver enzyme to a value similar to that of the bacterial enzyme. Further, it is shown that the intraliposomal nucleotides influence the kinetics of ferrocytochrome c oxidation by the reconstituted enzyme from bovine heart but not from P. denitrificans. The regulatory function attributed to the nuclear-coded subunits of mammalian cytochrome c oxidase is also demonstrated by the tissue-specific response of the reconstituted enzyme from bovine heart but not from bovine liver to intraliposomal ADP. These enzymes from bovine heart and liver differ in the amino acid sequences of subunits VIa, VIIa, and VIII. The results presented here are taken to indicate a regulation of cytochrome c oxidase activity by nuclear-coded subunits which act like receptors for allosteric effectors and influence the catalytic activity of the core enzyme via conformational changes.

Animals↗
PubMed2026

Ant abaecin-2 is a context-dependent copper-binding effector that can be either inhibitory or protective.

Host defense peptides (HDPs) are important components of the innate immune system that are used to combat pathogens and often rely on binding trace nutrient metals for their function. However, controlling nutrient metals may have other roles in host-symbiont interactions beyond poisoning harmful pathogens. This study characterizes the evolution, structural properties, and biochemical activity of the novel hymenopteran HDP abaecin-2. In myrmicine ants such as the fungus-growing tribe Attini, abaecin-2 has evolved to include an Amino-Terminal Cu(ii) and Ni(ii)-binding (ATCUN) motif, which we hypothesize binds copper, a trace nutrient that is enriched in attine ant colonies. Combined results from mass spectrometry, competitive binding assays, circular dichroism, and NMR indicate that the abaecin-2 peptide lacks a defined secondary structure and can associate with up to 2 Cu(ii) ions, one strongly bound at the ATCUN motif and another weakly bound, likely at a conserved histidine residue. Despite its copper-binding activity, abaecin-2 alone does not exhibit antibacterial activity against Escherichia coli or Bacillus subtilis (models for bacteria that live in ant fungus gardens). However, it synergizes with a model pore-forming peptide cecropin A to inhibit the growth of E. coli, similar to the related peptide abaecin-1. The copper-binding activity conferred by the ATCUN motif also protects copper-sensitive E. coli from excess copper toxicity. The dual context-dependent inhibitory and protective roles for abaecin-2 indicate that this previously under-characterized HDP may be used by attine ants to regulate both harmful and beneficial symbionts.

Journal Article↗
PubMed1990

The evolution of inducible defence.

Defences against parasites are characterized by inducible, amplifiable responses, often with a memory component. Inducible defences with similar properties are common in a variety of other types of interactions, for example many aquatic invertebrates produce inducible structural defences against their predators and competitors. Most inducible defences have the following properties: (1) a threshold of activation; (2) an amplification of response with increasing stimulus; (3) a memory component. Specificity, amplification and memory are the basis for defining a defence as 'immune' (Klein, 1982), and these properties are present in both the vertebrate and invertebrate internal defence responses to pathogens. Invertebrates differ in the absence of immunoglobulins and therefore in reduced specificity. Although the reduced specificity of invertebrate internal defence systems is often viewed as proof of their 'primitiveness', the differences in defence systems of vertebrates and invertebrates may be more related to their respective selection regimes than to phylogeny. The syngeneic recognition system of vertebrates functions to recognize small departures from self, such as would arise from neoplasia. Are vertebrates under more intense selection from neoplasia, perhaps due to a greater incidence of hormonal imbalance or hypersensitivity reactions? The invertebrate internal defence systems are all less discriminating than the vertebrate, but there are marked differences in degree of discrimination depending on whether the group is colonial or not. Even the phyla of colonial animals with quite simple body plans, the sponges and cnidarians, have a more discriminating recognition system than the phyla of solitary animals with more complex body plans, such as the molluscs and arthropods. The primary effectors of all invertebrate responses to parasites are encapsulation and phagocytosis, although in some phyla there are specific antibacterial proteins than can also be induced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Receptors: the materialization of a concept.

The evolution of the receptor concept over the years, culminating in the materialization thereof is outlined step by step. Attention is paid to molecular pharmacology, affinity and intrinsic activity, partial agonists and partial antagonists, receptor differentiation, receptor kinetics, receptor dynamics, receptor-effector coupling and receptor reserve, localization, quantification and isolation of receptors. Receptor pathology includes 'inborn errors of receptor function', involvement of receptors in autoimmune diseases and in malignant diseases. Finally iatrogenic receptor imbalances are discussed.

Animals↗
PubMed2026

Ant abaecin-2 is a context-dependent copper-binding effector that can be either inhibitory or protective.

Host defense peptides (HDPs) are important components of the innate immune system that are used to combat pathogens and often rely on metal binding for their function. However, controlling trace nutrients such as transition metals may have other roles in host-symbiont interactions beyond poisoning harmful pathogens. This study characterizes the evolution, structural properties, and biochemical activity of the novel hymenopteran HDP abaecin-2. In myrmicine ants such as the fungus-growing tribe Attini, abaecin-2 has evolved to include an Amino-Terminal Cu(II) and Ni(II)-binding (ATCUN) motif, which we hypothesize may bind copper, a trace nutrient that is enriched in attine ant colonies. Combined results from mass spectrometry, competitive binding assays, circular dichroism, and NMR indicate that the abaecin-2 peptide lacks a defined secondary structure and can associate with up to 2 Cu(II) ions, one strongly bound at the ATCUN motif and another weakly bound, likely at a conserved histidine residue. Despite its copper-binding activity, abaecin-2 alone does not exhibit antibacterial activity against Escherichia coli or Bacillus subtilis (models for bacteria that live in ant fungus gardens). However, it synergizes with a model pore-forming peptide cecropin A to inhibit the growth of E. coli, similar to the related peptide abaecin-1. The copper-binding activity conferred by the ATCUN motif also protects copper-sensitive E. coli from excess copper toxicity. The dual, context-dependent inhibitory and protective roles we propose for abaecin-2 indicate that this previously under-characterized HDP may be used by attine ants to regulate both harmful and beneficial symbionts.

Journal Article↗
PubMed1984

[The reaction of antibody-dependent cell-mediated cytotoxicity (ADCC)].

The antibody-dependent cell-mediated cytotoxicity (ADCC) is a cytotoxic reaction mediated by non immune cells (effector cells) against target cells sensitized by antibodies which are specific of the target cells' surface antigens. Those antibodies belong mostly to the IgG class. Several kinds of leucocytes can play a role in ADCC. All of them bear a receptor for the Fc fragment of the immunoglobulins. The efficacy of each population of effector cells varies according to the animal species and the type of the target cell. Some ADCC effectors are very similar to the natural killers (NK) but they do not belong exactly to the same subpopulation. ADCC can be studied by an indirect method (Cr51 release) or by a direct visual method (single cell assay). Several substances can influence ADCC reactions: corticoids either do not modify or inhibit the reaction. Interferon does not interact with ADCC nor enhances it. Antibiotics do not influence the reaction. Complement enhances the ADCC. Complement reduces the concentration of antibodies and the number of effector cells required for lysis. ADCC plays a role in several biological processes like graft rejection, autoimmune diseases, antitumoral defence, antiparasitical defence, antiviral defence which seems to be its most important role in domestic animals. ADCC can be used to study the evolution of sensitizing antibodies following a viral infection.

Adrenal Cortex Hormones↗
PubMed1990

Pemphigus antibodies and shedding snake serum enhance susceptibility of epidermal keratinocytes in natural cytotoxic reactions.

In order to clarify the role of natural cytotoxicity (NC) in the damage of epidermal keratinocytes (EK) in pemphigus vulgaris (PV) we used the direct 51Cr-release assay in studying the cytotoxic activity of large grandular lymphocytes (LGL), obtained from 34 acute PV patients and 19 healthy donors against EK of PV patients, donors, intact newborn BALB/c mice and mice with experimental PV, shedding and non-shedding grass snakes. We also investigated the effect of pemphigus antibodies and shedding snake serum protein (SSSP) upon EK sensitivity to cytotoxic effects of NC effectors. In other experiments, studied were the amount of serine proteinase secreted by donor LGL in the presence of membrane antigen of antibody- or SSSP-transformed EK, and direct effect of pemphigus antibodies and SSSP upon the release of radioactive label and endoproteinases from EK. It was found that EK, which had interacted with pemphigus antibodies or SSSP, became a sensitive target for NC effectors. Membrane antigen of antibody- and SSSP-transformed human, murine and snake EK induces the secretion of endproteinases by NC effector cells. The conclusion was made that the effect of both pemphigus antibodies and SSSP on EK resulted in the emergences of a new antigen on EK cellular membrane which is recognized by NC effectors and plays the role of the ligand in receptor/ligand interaction between LGL and their targets.

Animals↗
PubMed1992

Concerted evolution of the mouse Tcp-10 gene family: implications for the functional basis of t haplotype transmission ratio distortion.

The mouse Tcr locus is defined by its central role in the transmission ratio distortion phenotype characteristic of t haplotypes. A molecular candidate for Tcr has been identified in the form of a gene--Tcp-10b--expressed during spermatogenesis. Tcp-10b is one member of a multigene family present in two to four copies on different homologs of chromosome 17. The coding regions of the Tcp-10 genes present within two inbred strains were compared with those of the tw5 haplotype. The various gene family members are highly conserved relative to each other with a minimum nucleotide identity of 98.6% in all pairwise comparisons. Maximal parsimony analysis indicates that the Tcp-10 gene family has evolved in a concerted manner with the obliteration of nearly all individual gene-specific characteristics. As a consequence, the candidate for the full-length mutant Tcr gene product is distinguished by only a single, highly conservative, amino acid change. The data are consistent with the hypothesis that the effector of mutant Tcr activity is a second, alternatively spliced product that is expressed in a haploid- and allele-specific manner.

Alleles↗
PubMedDate not supplied

[Elements of the genome regulating structural gene transcription in eukaryotes].

A constant fine regulation of gene expression is needed for the normal development to proceed and for the physiological homeostasis to be maintained. In many cases such a regulation in eukaryotes is realized at the level of transcription, involving various cis- and trans-regulatory genomic elements. The review provides the data on the structure of elements determining the level of gene transcription in response to the action of various environmental factors and effectors, responsible for coordinated expression of the genes which provide for tissue-specific transcription and self-regulation of gene transcription. The data were considered on regulation of gene activity by mobile genetic elements and a relationship between the mechanisms of regulation of gene expression and evolution has been formulated.

Animals↗
PubMed1980

Intracellular protein topogenesis.

Concurrently with or shortly after their synthesis on ribosomes, numerous specific proteins are unidirectionally translocated across or asymmetrically integrated into distinct cellular membranes. Thereafter, subpopulations of these proteins need to be sorted from each other and routed for export or targeted to other intracellular membranes or compartments. It is hypothesized here that the information for these processes, termed "protein topogenesis," is encoded in discrete "topogenic" sequences that constitute a permanent or transient part of the polypeptide chain. The repertoire of distinct topogenic sequences is predicted to be relatively small because many different proteins would be topologically equivalent-i.e., targeted to the same intracellular address. The information content of topogenic sequences would be decoded and processed by distinct effectors. Four types of topogenic sequences could be distinguished: signal sequences, stop-transfer sequences, sorting sequences, and insertion sequences. Signal sequences initiate translocation of proteins across specific membranes. They would be decoded and processed by protein translocators that, by virtue of their signal sequence-specific domain and their unique location in distinct cellular membranes, effect unidirectional translocation of proteins across specific cellular membranes. Stop-transfer sequences interrupt the translocation process that was previously initiated by a signal sequence and, by excluding a distinct segment of the polypeptide chain from translocation, yield asymmetric integration of proteins into translocation-competent membranes. Sorting sequences would act as determinants for posttranslocational traffic of subpopulations of proteins, originating in translocation-competent donor membranes (and compartments) and going to translocation-incompetent receiver membranes (and compartments). Finally, insertion sequences initiate unilateral integration of proteins into the lipid bilayer without the mediation of a distinct protein effector. Examples are given for topogenic sequences, either alone or in combination, to provide the information for the location of proteins in any of the intracellular compartments or for the asymmetric orientation of proteins and their location in any of the cellular membranes. Proposals are made concerning the evolution of topogenic sequences and the relationship of protein topogenesis to the precellular evolution of membranes and compartments.

Animals↗
PubMed2026

The factory enters the fray: how mitochondrial protein trafficking shapes the host response to infection.

Beyond textbook functions in homeostatic metabolism, mitochondria are now recognized as central coordinators of cell-intrinsic and cell-extrinsic immune responses to infection. Directed trafficking of proteins and other molecules between mitochondria and the rest of the cell underlies a growing catalog of these activities. Some are pro-host; others are antagonized by viral effectors or co-opted by viruses entirely. How host and viral factors rewire the mitochondrial proteome during infection to shape these outcomes remains incompletely understood. The evolutionary history of this system adds another dimension: mitochondria retain biochemical signatures of their α-proteobacterial endosymbiotic origin, and ongoing co-evolution between viral, host, and mitochondrial genomes continues to shape the proteins that traffic to and from the organelle. Using published examples, we highlight general principles, mechanisms, and consequences of host and viral protein localization to and from the mitochondria. To support discovery, we present integrated gene lists identifying host mitochondrial factors with evidence for type I interferon stimulation, interactions with viral proteins, and signatures of positive selection. Together, these resources and the principles within offer a framework for understanding mitochondria not as passive metabolic machinery but as actively contested cellular territory whose protein composition is continuously negotiated between the host and the pathogen.

adaptation↗
PubMed1992

Evolution of ruminant hemoglobins. Thermodynamic divergence of ox and buffalo hemoglobins.

The ligand-binding properties of hemoglobins from two homozygote phenotypes (AA and BB) of water buffalo (Bubalus bubalis) have been characterized by equilibrium and kinetic techniques. In the case of the BB phenotype, the two constituent hemoglobins have been purified and separately analysed. Buffalo hemoglobins display the reduced sensitivity to organic phosphates characteristic of ruminant hemoglobins, their physiological effector probably being the chloride ion. In contrast to the other known hemoglobins from ruminants, all the hemoglobins from the water buffalo display a significant temperature sensitivity, the delta H for oxygen binding in the presence of physiological effectors approaching that of human hemoglobin (delta H = -30.5 kJ/mol O2). This discrepancy with the other ruminant hemoglobins (e.g. ox, delta H = -10.4 kJ/mol O2), whose primary structure is very similar to that of buffalo, hemoglobins might be correlated to the different habitat and phylogenetic history of the two subfamilies (Bos and Bubalus) of Bovidae.

Animals↗
PubMed1989

Interleukin-2 alone and in combination with other cytokines in melanoma: the investigational approach at the University of Texas M.D. Anderson Cancer Center.

The clinical data that have been accumulated so far suggests a significant influence of IL-2 dose and schedule on the immunobiological effects and clinical toxicities observed with this cytokine. Consequently, the series of Phase I and Phase II clinical trials conducted at the University of Texas M. D. Anderson Cancer Center in patients with advanced malignant melanoma investigating the use of IL-2 in combination with other cytokines, monoclonal antibodies, or ex vivo activated effector cells have used a common dose and schedule of IL-2 administration for which abundant immunobiological information already exists. This approach allows cross-trial comparison of experience with toxicities, immunobiological observations and clinical activity by a group of investigators within a single institution, and more rapid and valid evolution towards combination biological therapy, which preclinical data suggest will have greater activity than single agent therapy.

Biological Factors↗