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J M Berger

Publications and source records attributed to J M Berger.

At least 37 records · Page 2Linked to original sources
PubMed1998

Structural similarities between topoisomerases that cleave one or both DNA strands.

Type IA and type II DNA topoisomerases are distinguished by their ability to cleave one or two strands, respectively, of a DNA duplex. Both types have been proposed to use an "enzyme-bridging" mechanism, in which a break is formed in a DNA strand and a gap is opened between the broken pieces to allow passage of a second DNA strand or duplex segment. Although the type IA and type II topoisomerase structures appear overall quite different from one another, unexpected similarities between several structural elements suggest that members of the two subfamilies may use comparable mechanisms to bind and cleave DNA.

Binding Sites↗
PubMed1998

Computational learning reveals coiled coil-like motifs in histidine kinase linker domains.

The recent rapid growth of protein sequence databases is outpacing the capacity of researchers to biochemically and structurally characterize new proteins. Accordingly, new methods for recognition of motifs and homologies in protein primary sequences may be useful in determining how these proteins might function. We have applied such a method, an iterative learning algorithm, to analyze possible coiled coil domains in histidine kinase receptors. The potential coiled coils have not yet been structurally characterized in any histidine kinase, and they appear outside previously noted kinase homology regions. The learning algorithm uses a combination of established sequence patterns in known coiled coil proteins and histidine kinase sequence data to learn to recognize efficiently this coiled coil-like motif in the histidine kinases. The common appearance of the structural motif in a functionally important part of the receptors suggests hypotheses for kinase regulation and signal transduction.

Algorithms↗
PubMed1998

Type II DNA topoisomerases.

Type II DNA topoisomerases are enzymes capable of passing one DNA duplex through another. A combination of structural and biochemical analyses is illuminating the mechanistic details of this transport reaction, revealing the sites of DNA and nucleotide binding and the existence of large-scale domain motions.

Archaeal Proteins↗
PubMed1997

Structure of a murine leukemia virus receptor-binding glycoprotein at 2.0 angstrom resolution.

An essential step in retrovirus infection is the binding of the virus to its receptor on a target cell. The structure of the receptor-binding domain of the envelope glycoprotein from Friend murine leukemia virus was determined to 2.0 angstrom resolution by x-ray crystallography. The core of the domain is an antiparallel beta sandwich, with two interstrand loops forming a helical subdomain atop the sandwich. The residues in the helical region, but not in the beta sandwich, are highly variable among mammalian C-type retroviruses with distinct tropisms, indicating that the helical subdomain determines the receptor specificity of the virus.

Amino Acid Sequence↗
PubMed1997

Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module.

The low-density lipoprotein receptor (LDLR) is responsible for the uptake of cholesterol-containing lipoprotein particles into cells. The amino-terminal region of LDLR, which consists of seven tandemly repeated, approximately 40-amino-acid, cysteine-rich modules (LDL-A modules), mediates binding to lipoproteins. LDL-A modules are biologically ubiquitous domains, found in over 100 proteins in the sequence database. The structure of ligand-binding repeat 5 (LR5) of the LDLR, determined to 1.7 A resolution by X-ray crystallography and presented here, contains a calcium ion coordinated by acidic residues that lie at the carboxy-terminal end of the domain and are conserved among LDL-A modules. Naturally occurring point mutations found in patients with the disease familial hypercholesterolaemia alter residues that directly coordinate Ca2+ or that serve as scaffolding residues of LR5.

Amino Acid Sequence↗
PubMed1997

Core structure of gp41 from the HIV envelope glycoprotein.

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) consists of a complex of gp120 and gp41. gp120 determines viral tropism by binding to target-cell receptors, while gp41 mediates fusion between viral and cellular membranes. Previous studies identified an alpha-helical domain within gp41 composed of a trimer of two interacting peptides. The crystal structure of this complex, composed of the peptides N36 and C34, is a six-helical bundle. Three N36 helices form an interior, parallel coiled-coil trimer, while three C34 helices pack in an oblique, antiparallel manner into highly conserved, hydrophobic grooves on the surface of this trimer. This structure shows striking similarity to the low-pH-induced conformation of influenza hemagglutinin and likely represents the core of fusion-active gp41. Avenues for the design/discovery of small-molecule inhibitors of HIV infection are directly suggested by this structure.

Amino Acid Sequence↗
PubMed1996

DNA transport by a type II topoisomerase: direct evidence for a two-gate mechanism.

Recent biochemical and crystallographic results suggest that a type II DNA topoisomerase acts as an ATP-modulated clamp with two sets of jaws at opposite ends: a DNA-bound enzyme can admit a second DNA through one set of jaws; upon binding ATP, this DNA is passed through an enzyme-mediated opening in the first DNA and expelled from the enzyme through the other set of jaws. Experiments based on the introduction of reversible disulfide links across one dimer interface of yeast DNA topoisomerase II have confirmed this mechanism. The second DNA is found to enter the enzyme through the gate formed by the N-terminal parts of the enzyme and leave it through the gate close to the C termini.

Adenosine Triphosphate↗
PubMed1996

Structure and mechanism of DNA topoisomerase II.

The crystal structure of a large fragment of yeast type II DNA topoisomerase reveals a heart-shaped dimeric protein with a large central hole. It provides a molecular model of the enzyme as an ATP-modulated clamp with two sets of jaws at opposite ends, connected by multiple joints. An enzyme with bound DNA can admit a second DNA duplex through one set of jaws, transport it through the cleaved first duplex, and expel it through the other set of jaws.

Adenosine Triphosphatases↗
PubMed1996

Recent developments in DNA topoisomerase II structure and mechanism.

Type II DNA topoisomerases are enzymes that are capable of transporting one duplex DNA through another. Recent experimental results, including the structure of a fragment of yeast topoisomerase II, have provided new insights into the mechanism of the strand passage reaction. Other results have begun to define the role of ATP in the catalytic cycle and illuminate how DNA breaks mediated by topoisomerase II can occur.

Adenosine Triphosphate↗
PubMed1994

Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp.

The mechanism of inhibition of eukaryotic DNA topoisomerase II [DNA topoisomerase (ATP-hydrolyzing), EC 5.99.1.3] by a member of the bisdioxopiperazine family of anticancer drugs, ICRF-193, was investigated by using purified yeast DNA topoisomerase II. In the absence of ATP, ICRF-193 has little effect on the binding of the enzyme to various forms of DNA. In the presence of ATP, the drug converts the enzyme to a form incapable of binding circular DNA. Incubation of a preformed circular DNA-enzyme complex with ICRF-193 and ATP converts the complex to a form stable in molar concentrations of salt. These results can be interpreted in terms of the ATP-modulated protein-clamp model of type II DNA topoisomerases [Roca, J. & Wang, J. C. (1992) Cell 71, 833-840]; ICRF-193 can bind to the closed-clamp form of the enzyme and prevents its conversion to the open-clamp form. This interpretation is further supported by the finding that whereas both ATP and the drug are needed to form the salt-stable circular DNA-enzyme complex, ATP is not needed for maintaining this complex; furthermore, a signature of the closed-clamp form of the enzyme, Staphylococcus aureus strain V8 endoproteinase cleavage site at Glu-680, is observed if the enzyme is incubated with both ATP and ICRF-193. Inhibition of interconversion between the open- and closed-clamp forms of type II DNA topoisomerases offers a new mechanism in the selection and design of therapeutics targeting this class of enzymes.

Adenosine Triphosphate↗
PubMed1993

On the simultaneous binding of eukaryotic DNA topoisomerase II to a pair of double-stranded DNA helices.

Stabilization of crossings of pairs of DNA helices by binding of eukaryotic DNA topoisomerase II was studied by two types of experiments. In one, mixtures of yeast DNA topoisomerase II and supercoiled DNA were incubated with vaccinia virus topoisomerase, and the linking numbers of the DNA products were measured to quantitate supercoils that were constrained by the stoichiometrically bound yeast enzyme molecules; in parallel, the same yeast enzyme-supercoiled DNA mixtures were incubated with a nonhydrolyzable ATP analog AMPPNP (adenosine 5'-(beta, gamma-imido)triphosphate) instead of the vaccinia enzyme, and DNA linking number changes following the addition of AMPPNP were measured to monitor DNA transport mediated by the yeast enzyme and AMPPNP. In the second type of experiments, formation of knotted DNA rings by the addition of AMPPNP to mixtures of yeast DNA topoisomerase II and different topological forms of DNA rings was studied. These experiments indicate that binding of yeast DNA topoisomerase II to DNA crossings is significant, especially in low salt media containing Mg(II), and that this mode of binding strongly affects DNA knotting. It appears, however, that stabilization of DNA crossovers by the eukaryotic type II enzyme is not directly related to its DNA transport activity.

Adenylyl Imidodiphosphate↗
PubMed1992

Genetic dissection of pancreatic trypsin inhibitor.

In a previous study, a genetic screening procedure was used to identify variants of bovine pancreatic trypsin inhibitor that can fold to an active conformation but that are inactivated much more rapidly than the wild-type protein in the presence of dithiothreitol (DTT). The mechanisms by which 30 of these DTT-sensitive variants are inactivated have now been investigated. Some of the amino acid replacements cause rapid inactivation in the presence of DTT because the three disulfides of the native protein are reduced up to 300-fold faster than for the wild-type protein, leading to complete unfolding. Other substitutions, however, do not greatly increase the rate of complete reduction and unfolding but lead to accumulation of an inactive two-disulfide species. There is a striking correlation between the locations of the DTT-sensitive amino acid replacements in the three-dimensional structure of the protein and the mechanisms by which the variants are inactivated. All of the substitutions that cause rapid unfolding are clustered at one end of the folded protein, in the vicinity of the two disulfides that are reduced most slowly during unfolding of the wild-type protein, while substitutions of the other class are all located at the other end of the protein, near the trypsin binding site. These results indicate that the kinetic stability of native bovine pancreatic trypsin inhibitor and its ability to function as a protease inhibitor are largely influenced by residues in two distinguishable regions of the folded protein.

Amino Acid Sequence↗
PubMed1990

Bilateral processing of numbers: parallel processing versus functional unity.

Thirty-six normal subjects had to add two numbers ranging from 3 to 9 which were presented tachistoscopically. The two numbers were displayed either unilaterally to the left or right visual field, or bilaterally with one number to the left and one to the right visual field. They were represented as two word names, two dot clusters, or two bargraphs, or the two numbers were represented inconsistently in two different of these representations. The results showed that bilateral processing of a word and a bargraph was performed without visible interactions, and the hemispheres performed independently. When the display included a dot cluster, however, its processing (sequential vs. holistic) appeared to depend on the type of stimulus processed by the contralateral hemisphere, indicating strong interhemispheric interactions.

Adult↗
PubMed1988

Interhemispheric cooperation and activation in integration of verbal information.

Subjects had to judge the semantic relation between two tachistoscopically presented German adjectives. In Exp. I, the two words were projected simultaneously, either both to the left visual field (i.e. to the right hemisphere, LVF-RH), or both to the right visual field (i.e. to the left hemisphere, RVF-LH), or one word to each visual field (i.e. to both hemispheres, EVF-BH). The results yielded a significantly higher performance in the condition EVF-BH than in the two unilateral conditions, without a significant difference between the latter two conditions. In Exp. II, the two words were shown successively. With bilateral presentation, a distinction was made as to whether the left visual field (EVF-BH-L) or the right visual field (EVF-BH-R) was stimulated first. The significantly highest performance was shown in conditions RVF-LH and EVF-BH-R compared with the condition EVF-BH-L, and the significantly poorest performance in the condition LVF-RH compared with the condition EVF-BH-L. The results provide evidence for (1) an intrahemispheric interference with simultaneous unilateral presentation, (2) a cooperative interhemispheric interaction with simultaneous bilateral presentation, and (3) an interhemispheric priming effect with successive bilateral presentation when the left hemisphere was stimulated first.

Adult↗
PubMed1988

Role of interstimulus and stimulus-hemisphere compatibility in the process of interhemispheric integration.

Normal subjects had to name German compound nouns which were presented tachistoscopically. The compound nouns were displayed either unilaterally to the left or right visual field, or bilaterally with one element to the left and one to the right visual field. A distinction was made between the bilateral conditions as to whether the representation of the elements, printed and/or pictorial, included a high or low interstimulus and a high or low stimulus-hemisphere compatibility. Analysis indicated firstly a superiority of the left hemisphere for the naming of compound nouns in mixed print and pictorial representation. Secondly, the performance in the bilateral conditions was moderated by stimulus-hemisphere compatibility. In the process of interhemispheric integration stimulus-hemisphere compatibility proved more crucial than interstimulus compatibility. Analyses of errors further illustrated hemispheric behaviour.

Adult↗