PubMed Health⌕ Search

Biomedical subjects

J M Berg

Publications and source records attributed to J M Berg.

At least 19 recordsLinked to original sources
PubMed1992

Monozygotic twins concordant for late-onset probable Alzheimer disease with suspected Alzheimer disease in four sibs.

Probable Alzheimer disease (AD) is described in 79-year-old male twins with monozygosity confirmed by DNA examination. The first twin to be affected began to show signs of intellectual deterioration at age 70. In the other, onset was at age 72. Four of their living sibs (current age range = 75-92) are also suspected to have AD. The possible roles of genetic and environmental factors in the development of AD in this sibship are discussed.

Aged↗
PubMed1992

Toward rules relating zinc finger protein sequences and DNA binding site preferences.

Zinc finger proteins of the Cys2-His2 type consist of tandem arrays of domains, where each domain appears to contact three adjacent base pairs of DNA through three key residues. We have designed and prepared a series of variants of the central zinc finger within the DNA binding domain of Sp1 by using information from an analysis of a large data base of zinc finger protein sequences. Through systematic variations at two of the three contact positions (underlined), relatively specific recognition of sequences of the form 5'-GGGGN(G or T)GGG-3' has been achieved. These results provide the basis for rules that may develop into a code that will allow the design of zinc finger proteins with preselected DNA site specificity.

Amino Acid Sequence↗
PubMed1992

Metal binding and folding properties of a minimalist Cys2His2 zinc finger peptide.

A minimalist Cys2His2 zinc finger peptide, Lys-Tyr-Ala-Cys-Ala-Ala-Cys-Ala-Ala-Ala-Phe-Ala-Ala-Lys-Ala-Ala-Leu-Ala- Ala-His-Ala-Ala-Ala-His-Ala-Lys, has been synthesized. Metal binding studies using Co2+ as a probe indicated that this peptide forms a 1:1 peptide/metal complex with a dissociation constant comparable to that observed for other zinc finger peptides. At high peptide concentrations, a 2:1 peptide/metal complex also forms, with four cysteinates coordinated to Co2+. Additional studies with sequence variants in which the canonical hydrophobic residues were changed to alanine, or in which one of the residues between the cysteines and the histidines was deleted, revealed an even more pronounced formation of the 2:1 complex over the 1:1 complex. In addition, the absorption spectra of the 1:1 peptide/Co2+ complexes of the variant peptides are significantly different from those seen for complexes of the parent peptide or those of more typical zinc finger peptides. NMR studies revealed that the parent peptide folds in the presence of Zn2+ to a structure very similar to that observed for other zinc finger peptides of this class. Taken together, these results suggest that the metal-binding and canonical hydrophobic residues are necessary and sufficient to determine the structure of this class of zinc finger peptides.

Amino Acid Sequence↗
PubMed1992

Redesigning the DNA-binding specificity of a zinc finger protein: a data base-guided approach.

A peptide corresponding to the three zinc finger domains of the human transcription factor Sp1 has been expressed and found to bind a consensus Sp1 binding site with the sequence 5'-GGGGCGGGG-3'. Examination of the amino acid distributions within a large zinc finger sequence data base and chemical arguments suggested that a particular Arg to Gln sequence change might convert binding specificity to 5'-GGGGCAGGG-3'. Experimental tests of this hypothesis revealed that such a change could be induced only when two other sequence changes, deduced from examination of sequence correlations, were made as well. These results provide the most direct information to date about how zinc finger proteins might recognize adenine-containing binding sites and bear on the existence and nature of any code between zinc finger protein and binding site sequences.

Amino Acid Sequence↗
PubMed1992

Molecular cloning of the recA gene and construction of a recA strain of Francisella novicida.

A gene locus that is functionally analogous to the recA gene of Escherichia coli was molecularly cloned from Francisella novicida. The cloned gene was found to suppress the sensitivity of an E. coli strain to DNA-damaging agents and to support genetic recombination in E. coli. After transposon mutagenesis, the recA-like gene locus was returned to F. novicida and a UV-sensitive F. novicida strain was isolated. In contrast to the wild-type strain, this UV-sensitive strain could not be transformed with chromosomal DNA.

Cloning, Molecular↗
PubMed1991

Family with 22-derived marker chromosome and late-onset dementia of the Alzheimer type: I. Application of a new model for estimation of the risk of disease associated with the marker.

We have identified 2 sisters with probable dementia of the Alzheimer type who have an unusual 22-derived marker chromosome with a greatly elongated short arm containing 2 well-separated nucleolus organizer regions. A marker chromosome similar in appearance is uncommon in the general population. Eleven of 24 of their biological relatives were also found to have the marker. The known pedigree of this family encompasses 6 generations in 2 of which there is evidence of 10 cases of dementia of the Alzheimer type. The average age-at-onset of dementia is 65.8 +/- 5.5 years; the average age-at-death among those apparently affected is 74.9 +/- 8.3 years. A new model for the estimation of risk was applied to the family data. Persons in this family with the marker were found to be 4 times more likely to develop dementia than those without the marker, the 95% confidence interval for this risk being 1-50. The probability that the association of dementia and the marker is due to chance alone is .05 (1 in 20).

Aged↗
PubMed1991

Identification and characterization of "zinc-finger" domains by the polymerase chain reaction.

We have developed a method for amplifying DNA fragments containing tandem arrays of "zinc-finger" sequences of the transcription factor IIIA (Cys2-His2) type by using the polymerase chain reaction. Because these sequences occur as tandem arrays, a ladder of bands is produced upon amplification using primers derived from the amino- and carboxyl-terminal sequences of a zinc-finger domain. The "rungs" of this ladder correspond to DNA fragments encoding one zinc-finger domain, two adjacent zinc-finger domains, and so on. This is demonstrated by isolating individual bands corresponding to n zinc-finger domains and reamplifying them with the same primers. This yields a band of the original size as well as bands corresponding to 1 through (n - 1) zinc-finger domains. Direct evidence that these bands encode zinc-finger domains was obtained by cloning and sequencing a collection of the amplification products. Due to the lack of redundancy in the sequences obtained, we conclude that each band corresponds to a large number of unique zinc-finger-encoding sequences. The results from amplification reaction mixtures using genomic DNA from a variety of sources as template provide further evidence that zinc-finger domains occur widely and frequently in eukaryotic genomes. We believe that this method is a powerful technique for the isolation and characterization of zinc-finger-encoding genes.

Amino Acid Sequence↗
PubMed1991

A family with multiple instances of definite, probable and possible early-onset Alzheimer's disease.

A family with a multigenerational history of proven or suspected early-onset Alzheimer's disease (AD) consistent with autosomal-dominant inheritance is described. To date, the pedigree comprises five generations in which there are 13 known affected individuals. The mean age of onset of cognitive deficits in those for whom data are available (n = 11) is 47.6 (s.d. 3.0) years and the mean age of death (n = 10) is 58.8 (s.d. 4.0) years. The variability in the extent and quality of available data illustrates the diagnostic difficulties encountered in ascertaining such an extended pedigree, and the need for caution in interpreting the evidence.

Adult↗
PubMed1990

Retroviral nucleocapsid protein-metal ion interactions: folding and sequence variants.

Retroviral nucleocapsid proteins contain one or two proposed metal-binding sequences of the form Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys. Previously, we reported that an 18-amino acid peptide derived from the nucleocapsid protein of Rauscher murine leukemia virus (RMLV) binds metals such as Co2+ and Zn2+. We have now synthesized the entire nucleocapsid protein from RMLV. We report here that the protein also binds Co2+ and Zn2+ and does so with a higher affinity than does the peptide. Limited proteolysis and circular dichroism studies reveal that metal binding induces folding of the metal-binding domain and, perhaps, the regions adjacent to it but the remainder of the protein remains in a relatively unstructured state. In addition, we have synthesized sequence variants of the metal-binding domain that correspond to viral mutations reported in the literature. In many cases, the metal-binding properties of these peptides correlate with the observed biological activity, providing further evidence for the importance of metal binding to nucleocapsid function.

Amino Acid Sequence↗
PubMed1990

Zinc finger domains: hypotheses and current knowledge.

Many of the hypotheses are clearly correct that are based on the initial observation that TFIIIA has an approximately periodic structure with invariant pairs of cysteines and histidines apparently capable of coordinating metal ions. A startling number of other cDNA clones encode proteins that contain one or more sequences that match the zinc finger consensus, revealing that zinc finger proteins represent perhaps the largest class of DNA binding proteins in eukaryotes and that zinc finger protein-controlled gene expression may be a fundamental aspect of development as well as other processes. A great deal of progress has been made in elucidating the structure of single zinc finger domains. From knowledge of these structures, plausible and testable models can be developed for the complexes between zinc finger proteins and their DNA binding sites. Clearly, one of the most important challenges remaining in this area involves testing and extending these models. Structural data on such protein-nucleic acid complexes derived from NMR or crystallographic studies is tremendously valuable in this regard. Finally, an additional fundamental question is raised by the observation that this family and other important nucleic acid binding proteins contain zinc ions bound in small structural domains. Is zinc binding merely a useful structural strategy for generating domains involved in macromolecular interactions, or are zinc concentration fluctuations used in some manner to regulate gene expression? The biophysical data available to date certainly do not rule out this intriguing possibility.

Amino Acid Sequence↗
PubMed1989

A retroviral Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys peptide binds metal ions: spectroscopic studies and a proposed three-dimensional structure.

Retroviral gag gene-encoded core nucleic acid binding proteins contain either one or two sequences of the form Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys. Previously, one of us has proposed that these sequences form metal-binding domains in analogy with the "zinc finger" domains first observed in transcription factor IIIA. We report that an 18-amino acid peptide derived from the core nucleic acid binding protein from Rauscher murine leukemia virus binds metal ions such as Co2+ and Zn2+. The absorption spectrum of the peptide-Co2+ complex is highly suggestive of tetrahedral coordination involving three cysteinates and one histidine. Titration experiments indicate that the dissociation constant for the peptide-Co2+ complex is 1.0 microM and that Zn2+ binds more tightly than Co2+. A detailed three-dimensional structure for this domain based on conserved substructures in other crystallographically characterized metalloproteins and on a detailed analysis of the Cys-Xaa2-Cys-Xaa4-His-Xaa4-Cys sequences from retroviruses and other related sources is proposed.

Amino Acid Sequence↗