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PubMed2003

Misfolded CuZnSOD and amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of motor neurons. The inherited form of the disease, familial ALS, represents 5-10% of the total cases, and the best documented of these are due to lesions in SOD1, the gene encoding copper-zinc superoxide dismutase (CuZnSOD). The mechanism by which mutations in SOD1 cause familial ALS is currently unknown. Two hypotheses have dominated recent discussion of the toxicity of ALS mutant CuZnSOD proteins: the oligomerization hypothesis and the oxidative damage hypothesis. The oligomerization hypothesis maintains that mutant CuZnSOD proteins are, or become, misfolded and consequently oligomerize into increasingly high-molecular-weight species that ultimately lead to the death of motor neurons. The oxidative damage hypothesis maintains that ALS mutant CuZnSOD proteins catalyze oxidative reactions that damage substrates critical for viability of the affected cells. This perspective reviews some of the properties of both wild-type and mutant CuZnSOD proteins, suggests how these properties may be relevant to these two hypotheses, and proposes that these two hypotheses are not necessarily mutually exclusive.

Humans↗

PubMed2006

The coiled-coil domain of the Nop56/58 core protein is dispensable for sRNP assembly but is critical for archaeal box C/D sRNP-guided nucleotide methylation.

Archaeal box C/D sRNAs guide the methylation of specific nucleotides in archaeal ribosomal and tRNAs. Three Methanocaldococcus jannaschii sRNP core proteins (ribosomal protein L7, Nop56/58, and fibrillarin) bind the box C/D sRNAs to assemble the sRNP complex, and these core proteins are essential for nucleotide methylation. A distinguishing feature of the Nop56/58 core protein is the coiled-coil domain, established by alpha-helices 4 and 5, that facilitates Nop56/58 self-dimerization in vitro. The function of this coiled-coil domain has been assessed for box C/D sRNP assembly, sRNP structure, and sRNP-guided nucleotide methylation by mutating or deleting this protein domain. Protein pull-down experiments demonstrated that Nop56/58 self-dimerization and Nop56/58 dimerization with the core protein fibrillarin are mutually exclusive protein:protein interactions. Disruption of Nop56/58 homodimerization by alteration of specific amino acids or deletion of the entire coiled-coil domain had no obvious effect upon core protein binding and sRNP assembly. Site-directed mutation of the Nop56/58 homodimerization domain also had no apparent effect upon either box C/D RNP- or C'/D' RNP-guided nucleotide modification. However, deletion of this domain disrupted guided methylation from both RNP complexes. Nuclease probing of the sRNP assembled with Nop56/58 proteins mutated in the coiled-coil domain indicated that while functional complexes were assembled, box C/D and C'/D' RNPs were altered in structure. Collectively, these experiments revealed that the self-dimerization of the Nop56/58 coiled-coil domain is not required for assembly of a functional sRNP, but the coiled-coil domain is important for the establishment of wild-type box C/D and C'/D' RNP structure essential for nucleotide methylation.

Amino Acid Sequence↗

PubMed1989

Identification of a mutation in Escherichia coli F1-ATPase beta-subunit conferring resistance to aurovertin.

A mutation conferring aurovertin resistance on Escherichia coli F1-ATPase was identified as R398----H in the F1 beta-subunit. Beta-subunit from the mutant does not bind aurovertin; therefore our results suggest the region of sequence around residue beta-398 is involved in aurovertin binding. Since nucleotide and aurovertin binding to isolated beta-subunit are not mutually exclusive, the data further suggest that the beta-subunit catalytic nucleotide-binding domain does not include residue 398. The mutation prevented aurovertin inhibition of ATPase at pH 6 and 8.5, implying charge on the arginine side-chain is not a major determinant of aurovertin binding or that the pK of R398 is shifted due to a peculiar environment. The equivalent residue is usually arginine in F1 beta-subunits of different species; notably in the aurovertin-insensitive thermophilic bacterium PS3 F1-ATPase, this residue is phenylalanine.

Aurovertins↗

PubMed2003

Specificity of binding of the plectin actin-binding domain to beta4 integrin.

Plectin is a major component of the cytoskeleton and links the intermediate filament system to hemidesmosomes by binding to the integrin beta4 subunit. Previously, a binding site for beta4 was mapped on the actin-binding domain (ABD) of plectin and binding of beta4 and F-actin to plectin was shown to be mutually exclusive. Here we show that only the ABDs of plectin and dystonin bind to beta4, whereas those of other actin-binding proteins do not. Mutations of the ABD of plectin-1C show that Q131, R138, and N149 are critical for tight binding of the ABD to beta4. These residues form a small cavity, occupied by a well-ordered water molecule in the crystal structure. The beta4 binding pocket partly overlaps with the actin-binding sequence 2 (ABS2), previously shown to be essential for actin binding. Therefore, steric interference may render binding of beta4 and F-actin to plectin mutually exclusive. Finally, we provide evidence indicating that the residues preceding the ABD in plectin-1A and -1C, although unable to mediate binding to beta4 themselves, modulate the binding activity of the ABD for beta4. These studies demonstrate the unique property of the plectin-ABD to bind to both F-actin and beta4, and explain why several other ABD-containing proteins that are expressed in basal keratinocytes are not recruited into hemidesmosomes.

Actins↗

PubMed1992

A novel base-pairing interaction between U2 and U6 snRNAs suggests a mechanism for the catalytic activation of the spliceosome.

Prior to the chemical steps of mRNA splicing, the extensive base-pairing interaction between the U4 and U6 spliceosomal snRNAs is disrupted. Here, we use a mutational analysis in yeast to demonstrate a conserved base-pairing interaction between the U6 and U2 snRNAs that is mutually exclusive with the U4-U6 interaction. In this novel pairing, conserved sequences in U6 interact with a sequence in U2 that is immediately upstream of the branch point recognition region. Remarkably, the residues in U6 that can be consequently juxtaposed with the intron substrate include those that have been proposed previously to be catalytic. Both the first and second steps of splicing are inhibited when this base-paired structure is mutated. These observations, together with the high conservation of the U2-U6 structure, lead us to propose that it might be a component of the spliceosomal active site.

Base Sequence↗

PubMed2006

Evidence for overdominant selection maintaining X-linked fitness variation in Drosophila melanogaster.

The role of balancing selection in maintaining genetic variation for fitness is largely unresolved. This reflects the inherent difficulty in distinguishing between models of recurrent mutation versus selection, which produce similar patterns of inbreeding depression, as well as the limitations of testing such hypotheses when fitness variation is averaged across the genome. Signatures of X-linked overdominant selection are less likely to be obscured by mutational variation because X-linked mutations are rapidly eliminated by purifying selection in males. Although models maintaining genetic variation for fitness are not necessarily mutually exclusive, a series of predictions for identifying X-linked overdominant selection can be used to separate its contribution from other underlying processes. We consider the role of overdominant selection in maintaining fitness variation in a sample of 12 X chromosomes from a population of Drosophila melanogaster. Substantial variation was observed for male reproductive success and female fecundity, with heterozygous-X genotypes exhibiting the greatest degree of variance, a finding that agrees well with predictions of the overdominance model. The importance of X-linked overdominant selection is discussed along with models of recurrent mutation and sexually antagonistic selection.

Alleles↗

PubMed2005

The yeast Hsp110 Sse1 functionally interacts with the Hsp70 chaperones Ssa and Ssb.

There is growing evidence that members of the extended Hsp70 family of molecular chaperones, including the Hsp110 and Grp170 subgroups, collaborate in vivo to carry out essential cellular processes. However, relatively little is known regarding the interactions and cellular functions of Sse1, the yeast Hsp110 homolog. Through co-immunoprecipitation analysis, we found that Sse1 forms heterodimeric complexes with the abundant cytosolic Hsp70s Ssa and Ssb in vivo. Furthermore, these complexes can be efficiently reconstituted in vitro using purified proteins. Binding of Ssa or Ssb to Sse1 was mutually exclusive. The ATPase domain of Sse1 was found to be critical for interaction as inactivating point mutations severely reduced interaction with Ssa and Ssb. Sse1 stimulated Ssa1 ATPase activity synergistically with the co-chaperone Ydj1, and stimulation required complex formation. Ssa1 is required for post-translational translocation of the yeast mating pheromone alpha-factor into the endoplasmic reticulum. Like ssa mutants, we demonstrate that sse1delta cells accumulate prepro-alpha-factor, but not the co-translationally imported protein Kar2, indicating that interaction between Sse1 and Ssa is functionally significant in vivo. These data suggest that the Hsp110 chaperone operates in concert with Hsp70 in yeast and that this collaboration is required for cellular Hsp70 functions.

Adenosine Triphosphatases↗

PubMed1995

Molecular dissection of the pseudoknot governing the translational regulation of Escherichia coli ribosomal protein S15.

The ribosomal protein S15 controls its own translation by binding to a mRNA region overlapping the ribosome binding site. That region of the mRNA can fold in two mutually exclusive conformations that are in dynamic equilibrium: a structure with two hairpins and a pseudoknot. A mutational analysis provided evidence for the existence and requirement of the pseudoknot for translational control in vivo and S15 recognition in vitro. In this study, we used chemical probing to analyze the structural consequences of mutations and their effect on the stem-loop/pseudoknot equilibrium. Interactions between S15 and the pseudoknot structure were further investigated by footprinting experiments. These data, combined with computer modelling and the previously published data on S15 binding and in vivo control, provide important clues on pseudoknot formation and S15 recognition. An unexpected result is that the relevant control element, here the pseudoknot form, can exist in a variety of topologically equivalent structures recognizable and shapable by S15. S15 sits on the deep groove of the co-axial stack and makes contacts with both stems, shielding the bridging adenine. The only specific sequence determinants are found in the helix common to the pseudoknot and the hairpin structures.

Base Sequence↗

PubMed1995

Alterations of multiple tumor suppressor genes (p53 (17p13), p16INK4 (9p21), and DBM (13q14)) in B-cell chronic lymphocytic leukemia.

B-cell chronic lymphocytic leukemia (B-CLL) samples were screened for alterations in multiple tumor suppressor genes (p53 (17p13), p16INK4 (9p21), and disrupted in B-cell malignancy (DBM) (13q14) by using polymerase chain reaction-based assays. Eleven percent (11 of 96) of the B-CLL cases analyzed in this study and a previous study had mutations in the p53 gene. In contrast, analysis of the p16 gene showed none of 80 B-CLL cases had mutations and five cases (6%) had homozygous deletions. Deletions of 13q14 (DBM) occurred in 18% (17 of 96) of patients surveyed. Thus, 28 of 96 cases showed an alteration in one or more of the three tumor suppressor loci examined. However, cases with p53 mutations rarely showed simultaneous loss of DBM. Our results suggest that inactivation of the tumor suppressor genes p53 and DBM may be mutually exclusive, thus providing alternate pathways for tumor development in B-CLL patients.

Base Sequence↗

PubMed1988

[Cell proliferation and cooperation of v-mil and v-myc oncogenes].

Retroviruses which possess the property to recombine with genetic material from the cell, have cloned and activated some oncogenes and hence are a privileged source for the study of these genes. Cellular oncogene activation can occur following two non mutually exclusive ways: (i) by over-expression of their products; (ii) by modifications of their products through mutations. Retroviruses can combine these two ways of activation leading to the over-expression of a modified product. In this paper, we present results obtained in the study of MH2, a retrovirus containing two oncogenes. We have shown that the two oncogenes of MH2 (v-mil and v-myc) cooperate in vitro to transform neuroretina cells from chicken embryos. These cells which normally do not grow in a defined medium, are induced to proliferate and become transformed upon infection by MH2. Our data enabled us to show that in MH2 v-mil was responsible for the induction of proliferation and v-myc for the transformation of the proliferating cells. Using in vitro constructs we located two regions in the protein encoded by v-mil which are important for its mitogenic property. We have also cloned the cellular counterpart of v-mil and the study of its biological activity on neuroretina cells enabled us to propose a mechanism of activation of the cellular gene by truncation of its 5' part.

Animals↗

PubMed1995

A ribonucleic antiterminator sequence (RAT) and a distant palindrome are both involved in sucrose induction of the Bacillus subtilis sacXY regulatory operon.

The Bacillus subtilis sacXY regulatory operon is involved in sucrose induction of the levansucrase sacB gene by an antitermination mechanism. In the presence of sucrose, the activated SacY antiterminator protein stabilizes the secondary structure of a ribonucleic antiterminator sequence (RAT) located in the leader region of the sacB transcript, and overlapping a rho-independent transcription terminator. Formation of the SacY-RAT complex prevents alternative formation of the terminator, allowing transcription of the downstream sequences. In the absence of sucrose, inhibition of SacY activity by SacX leads to termination of transcription. Expression of sacXY is also sucrose-inducible. This induction was previously shown to be mediated by SacY itself and/or SacT, another antiterminator involved in induction of genes belonging to a distinct sucrose pathway. These antiterminators are not activated at the same concentration of sucrose. We show here that sacXY induction occurs through activation of either SacY or SacT antiterminators, at their respective sucrose activation concentration. This result demonstrates a link between SacY- and SacT-mediated metabolic pathways. In addition, the sacXY leader region carries a RAT-like sequence, which however does not appear to overlap any apparent rho-independent transcription terminator. Site-directed mutagenesis experiments on this RAT-like sequence demonstrated its involvement in sucrose induction. Deletions generated in the sacXY leader region showed that a palindrome, located 100 nt downstream from the RAT-like sequence, also acts as a cis-acting element. Computer analysis of the leader RNA suggested that formation of the secondary structure of the RAT-like sequence and the palindrome could be mutually exclusive.

Bacillus subtilis↗

PubMed2005

Antimicrobial drug resistance: "Prediction is very difficult, especially about the future".

Evolution of bacteria towards resistance to antimicrobial drugs, including multidrug resistance, is unavoidable because it represents a particular aspect of the general evolution of bacteria that is unstoppable. Therefore, the only means of dealing with this situation is to delay the emergence and subsequent dissemination of resistant bacteria or resistance genes. Resistance to antimicrobial drugs in bacteria can result from mutations in housekeeping structural or regulatory genes. Alternatively, resistance can result from the horizontal acquisition of foreign genetic information. The 2 phenomena are not mutually exclusive and can be associated in the emergence and more efficient spread of resistance. This review discusses the predictable future of the relationship between antimicrobial drugs and bacteria.

Anti-Bacterial Agents↗

PubMed1995

Mutually exclusive interactions of two nuclear orphan receptors determine activity of a cyclic adenosine 3',5'-monophosphate-responsive sequence in the bovine CYP17 gene.

ACTH-dependent transcriptional activation of the bovine CYP17 gene (the gene encoding cytochrome P450 steroid 17 alpha-hydroxylase) involves two cAMP-responsive sequences (CRS1 and CRS2) located in the promoter region. Here we demonstrate that two nuclear orphan receptors, chicken ovalbumin upstream promoter transcription factor (COUP-TF) and steroidogenic factor-1 (SF-1), bind to the part of the CRS2 element that contains the repeated sequences AAGTCA and AGGTCA spaced by six nucleotides (repCRS2). Overexpression of COUP-TF and SF-1 in both steroidogenic and nonsteroidogenic cells demonstrated that SF-1 is an activator of repCRS2-dependent transcription of reporter genes. Furthermore, the SF-1-dependent transcription could be further stimulated by activation of the cAMP-dependent protein kinase. In contrast, COUP-TF alone had no effect on repCRS2-dependent reporter gene activity. Mutations that interfere with the binding of SF-1 to repCRS2 in vitro abolished the cAMP-induced activities mediated by the element in transfected Y1 cells. The mutational analysis of repCRS2 further indicated that the binding sites for the two receptors overlap, and electrophoretic mobility shift assays demonstrated that the receptors bound in a mutually exclusive manner. Overexpression of both SF-1 and COUP-TFI simultaneously demonstrated that COUP-TFI inhibited SF-1-dependent activation of reporter genes. Transient transfection experiments with a construct containing a -100/+19 base pair fragment from the bovine CYP17 gene demonstrated that SF-1 and COUP-TF had similar effects on the intact promoter as on the repCRS2/reporter gene constructs. Our data suggest that the two orphan receptors bind in a mutually exclusive manner to repCRS2 and that SF-1 is involved in the activation and COUP-TF in the repression of repCRS2-dependent transcription.

Animals↗

PubMed1997

Evidence for genetic control of Sonic hedgehog by Gli3 in mouse limb development.

Sonic hedgehog (Shh) expression in the developing limb is associated with the zone of polarising activity (ZPA), and both are restricted to the posterior part of the limb bud. We show that the expression patterns of Shh and Gli3, a member of the Gli-family believed to function in transcriptional control, appear to be mutually exclusive in limb buds of mouse embryos. In the polydactyly mouse mutant extra toes (Xt), possessing a null mutation of Gli3, Shh is additionally expressed in the anterior region of the limb bud. The transcript of Ptc, the putative receptor for Shh protein, can be detected anteriorly as well. Other genes known to be involved in limb outgrowth and patterning, like Fibroblast growth factor (Fgf), Bone morphogenetic protein (Bmp), and Hoxd are misexpressed in relation to the ectopic Shh expression domain in Xt limb buds. This data suggest that Gli3 is a regulator of Shh expression in mouse limb development.

Animals↗

PubMed1993

Postproliferative transcription of the rat osteocalcin gene is reflected by vitamin D-responsive developmental modifications in protein-DNA interactions at basal and enhancer promoter elements.

In the osteocalcin (OC) gene promoter, both independent positive and negative regulatory elements, as well as others with contiguous [TATA/glucocorticoid-responsive elements (GRE)] or overlapping [TATA/GRE, vitamin D-responsive enhancer elements (VDRE)/AP-1, and OC box/AP-1] domains, are sites for modifications in protein-DNA interactions. In the present studies, we have examined nuclear protein extracts from fetal rat calvarial cells that undergo a developmental sequence of bone cell differentiation. Our results demonstrate modifications in protein-DNA interactions that relate to the developmental stages of the osteoblast and support developmental regulation of OC gene transcription. Basal expression of the OC gene is associated with sequence-specific protein-DNA interactions at the OC box, VDRE, and TATA/GRE box. Distinct differences are observed in proliferating osteoblasts, where the OC gene is not transcribed compared to postproliferative, differentiated osteoblasts that transcribe the OC gene. Furthermore, the protein-DNA complexes that reflect hormonal control are also developmentally regulated, mediating both the transcriptionally active and repressed states of the OC gene. For example, in proliferating osteoblasts, a vitamin D receptor-antibody-sensitive complex is formed that is different from the DNA binding complex induced by vitamin D postproliferatively when the OC gene is transcribed. Mutational analysis of the steroid hormone binding domain and the overlapping AP-1 site at the VDRE supports mutually exclusive occupancy by Fos-Jun heterodimers and vitamin D receptor. Such protein-DNA interactions at the VDRE are consistent with repression of competency for vitamin D-mediated transcriptional enhancement in proliferating osteoblasts expressing high levels of Fos and Jun.

Animals↗

PubMed2001

Mutations in the TAR hairpin affect the equilibrium between alternative conformations of the HIV-1 leader RNA.

The HIV-1 untranslated leader RNA can adopt two mutually exclusive conformations that represent alternative secondary structures. This leader RNA can fold either an extended duplex through long-distance base pairing or a branched conformation in which the RNA locally folds into hairpin structures. Both leader RNA conformations have the TAR hairpin in common, which forms the extreme 5' end of all HIV-1 transcripts. We report that truncation of the TAR hairpin shifts the equilibrium between the two RNA conformations away from the thermodynamically favored long-distance interaction. However, the equilibrium is partially restored in response to the cations Na(+) and Mg(2+). The transcripts with mutant TAR structures allowed us to investigate conditions affecting the competition between the alternative conformations of the HIV-1 leader RNA. We also demonstrate that the change in conformation of the leader RNA due to TAR truncations severely affects formation of the HIV-1 RNA dimer.

Base Pairing↗

PubMed2003

Pathogenetic and biologic significance of TP14ARF alterations in nonsmall cell lung carcinoma.

The INK4a/ARF locus on human chromosome band 9p21 carries two tumor suppressor genes, TP14ARF and TP16INK4a, and both are frequently inactivated in nonsmall cell lung carcinoma (NSCLC. TP14ARF and TP16INK4a play important roles in the TP53 and RB tumor suppressor pathways, respectively. To elucidate the genetic and epigenetic status of the TP14ARF and TP16INK4a genes in NSCLC, we comprehensively analyzed mutations, homozygous deletions, methylations in the CpG regions, and expression of the TP14ARF and TP16INK4a genes in 31 NSCLC cell lines. TP16INK4a (84%) was inactivated more frequently than TP14ARF (55%). Moreover, p16INK4a was inactivated in all 17 cell lines with TP14ARF inactivation. Three cell lines with base substitutions in exon 2 resulted in missense mutations of TP16INK4a but silent mutations of TP14ARF. There was a case of mutation in exon 1alpha unique to TP16INK4a, but not a mutation in exon 1beta unique to TP14ARF. The TP16INK4a gene was methylated in 6 cell lines, but the TP14ARF gene was not methylated in any cell line. Unlike a mutually exclusive relationship for inactivation between TP16INK4a and RB, TP14ARF and TP53 did not show such a relationship (P = 0.61, Fisher exact test). Thus, the present results indicate the TP16INK4a gene to be the primary target of INK4a/ARF locus alterations. Transient TP14ARF expression induced G1 arrest in the cells with wild-type TP53, but not in the cells with mutated TP53. Thus, the pathogenetic and biologic significance of TP14ARF inactivation is different between NSCLC cells with wild-type TP53 and those with mutated TP53.

Blotting, Western↗

PubMed2006

The role of MYH and microsatellite instability in the development of sporadic colorectal cancer.

Biallelic germline mutations in MYH are associated with colorectal neoplasms, which develop through a pathway involving somatic inactivation of APC. In this study, we investigated the incidence of the common MYH mutations in an Australian cohort of sporadic colorectal cancers, the clinicopathological features of MYH cancers, and determined whether inactivation of mismatch repair and base excision repair (BER) were mutually exclusive. The MYH gene was sequenced from lymphocyte DNA of 872 colorectal cancer patients and 478 controls. Two compound heterozygotes were identified in the cancer population and all three cancers from these individuals displayed a prominent infiltration of intraepithelial lymphocytes. In total, 11 heterozygotes were found in the cancer group and five in the control group. One tumour from an individual with biallelic germline mutation of MYH also demonstrated microsatellite instability (MSI) as a result of biallelic hypermethylation of the MLH1 promoter. Although MYH-associated cancers are rare in a sporadic colorectal population, this study shows that these tumours can develop through either a chromosomal or MSI pathway. Tumours arising in the setting of BER or mismatch repair deficiency may share a biological characteristic, which promotes lymphocytic infiltration.

Adaptor Proteins, Signal Transducing↗