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PubMed2001

Heparan sulfate: decoding a dynamic multifunctional cell regulator.

The heparan sulfates are a family of cell-surface and matrix polysaccharides with an incredible degree of structural diversity that are distributed widely in virtually all metazoan organisms. Recent genetic, biochemical and cell-biological studies have led to increased understanding of the biosynthetic mechanisms that produce these complex molecules, as well as their functional versatility in regulating protein activities. The dynamic expression of heparan sulfates with differing sugar sequences suggests a new concept in which the repertoire of sequences produced by a particular cell or tissue is designated its 'heparanome'. This review discusses recent developments and surveys emerging experimental strategies that hold promise for revealing the functional specificity and mechanisms of action of heparan sulfates as multifunctional cell regulators.

Animals↗
PubMed1996

Transfer RNA structural change is a key element in the reassignment of the CUG codon in Candida albicans.

The human pathogenic yeast Candida albicans and a number of other Candida species translate the standard leucine CUG codon as serine. This is the latest addition to an increasing number of alterations to the standard genetic code which invalidate the theory that the code is frozen and universal. The unexpected finding that some organisms evolved alternative genetic codes raises two important questions: how have these alternative codes evolved and what evolutionary advantages could they create to allow for their selection? To address these questions in the context of serine CUG translation in C.albicans, we have searched for unique structural features in seryl-tRNA(CAG), which translates the leucine CUG codon as serine, and attempted to reconstruct the early stages of this genetic code switch in the closely related yeast species Saccharomyces cerevisiae. We show that a purine at position 33 (G33) in the C.albicans Ser-tRNA(CAG) anticodon loop, which replaces a conserved pyrimidine found in all other tRNAs, is a key structural element in the reassignment of the CUG codon from leucine to serine in that it decreases the decoding efficiency of the tRNA, thereby allowing cells to survive low level serine CUG translation. Expression of this tRNA in S.cerevisiae induces the stress response which allows cells to acquire thermotolerance. We argue that acquisition of thermotolerance may represent a positive selection for this genetic code change by allowing yeasts to adapt to sudden changes in environmental conditions and therefore colonize new ecological niches.

Base Sequence↗
PubMed1987

Unusual genetic codes and a novel gene structure for tRNA(AGYSer) in starfish mitochondrial DNA.

The nucleotide sequence of a 3849-bp fragment of starfish mitochondrial genome was determined. The genes for NADH dehydrogenase subunits 3, 4, 5, and COIII, and three kinds of (tRNA(UCNSer), tRNA(His), and tRNA(AGYSer) were identified by comparing with the genes of other animal mitochondria so far elucidated. The gene arrangement of starfish mitochondrial genome was different from those of vertebrate and insect mitochondrial genomes. Comparison of the protein-encoding nucleotide sequences of starfish mitochondria with those of other animal mitochondria suggested a unique genetic code in starfish mitochondrial genome; both AGA and AGG (arginine in the universal code) code for serine, AUA (isoleucine in the universal code but methionine in most mitochondrial systems) for isoleucine, and AAA (lysine) for asparagine. It was also inferred that these AGA and AGG codons are decoded by serine tRNA(AGYSer) originally corresponding to AGC and AGU codons. This situation is similar to the case of Drosophila mitochondrial genome. Variations in the use of AGA and AGG codons were discussed on the basis of the evolution of animals and decoding capacity of various tRNA(AGYSer) species possessing different sizes of the dihydrouridine (D) arm.

Animals↗
PubMed1998

[Genetic type of progressive hearing loss].

In daily practice we tend to underestimate hereditary factors as a cause of hearing impairment especially in those cases of late-onset and progressive hearing loss. Genetic hearing impairment may be congenital but it also may develop at any decade throughout life or deteriorate as part of a pre-existing congenital or acquired hearing impairment. Over the past 5 years, hereditary diseases associated with hearing impairment have been mapped, and several of genes have already been identified. Identification of genes causing hereditary deafness, as with other genetic diseases, goes through two stages: first mapping, then cloning. One method used to identify candidate genes based on their function or pattern of tissue expression involves the construction of cDNA libraries from the target organ or tissue, in this case from the cochlea. Studies of the molecular genetics of the inner ear are hampered by its relative inaccessibility, by the limited numbers of cochlear and vestibular cells, and by our inability to maintain many of these cell types in long term culture. The construction and characterization of cochlear cDNA libraries from humans and other species provide an important resource for rapid identification of cochlear genes involved in normal hearing and in hearing disorders; cDNA libraries constructed at different stages of development, and subtracted from each other, could be instrumental in identifying genes important at each stage of development of the cochlea. Libraries made from different tissues within an organ (i.e. inner vs outer hair cells) could be compared to identify genes that are needed for the differentiation of the cells into specific types. In addition, these libraries have the potential to foster identification of other proteins unique to the cochlea and will contribute to the identification, characterization, and functional analysis of these cochlea-specific proteins. Another important application of cDNA libraries is for identifying hearing loss genes. Once the candidate gene for a given type of hearing loss is cloned and decoded, the structure of its protein product can be determined. This will provide insights into biochemical function of the gene product in normal cochlear tissue, and will show why the genetic mutation result in hearing loss. Pedegree analysis and audiometric morphology have been widely used to attempt a subcategorisation of many isolated or familial "genetic" cases. A debatable point is the influence of aging on a genetic hearing loss. Effects due to genetic factors are often not easily distinguishable from the age-related factors. According to our findings, the progression of hearing loss present in several different patterns, according to the different interactions between hereditary hearing loss and presbycousis.

Adolescent↗
PubMed1993

Non-universal decoding of the leucine codon CUG in several Candida species.

It has been reported that CUG, a universal leucine codon, is read as serine in an asporogenic yeast, Candida cylindracea. The distribution of this non-universal genetic code in various yeast species was studied using an in vitro translation assay system with a synthetic messenger RNA containing CUG codons in-frame. It was found that CUG is used as a serine codon in six out of the fourteen species examined, while it is used for leucine in the remaining eight. The tRNA species responsible for the translation of codon CUG as serine was detected in all the six species in which CUG is translated as serine. The grouping according to the CUG codon assignments in these yeast species shows a good correlation with physiological classification by the chain lengths of the isoprenoid moiety of ubiquinone and the cell-wall sugar contained in the yeasts. The six Candida species examined in which CUG is used as serine belong to one distinct group in Hemiascomycetes.

Amino Acid Sequence↗
PubMed2003

A cryo-electron microscopic study of ribosome-bound termination factor RF2.

Protein synthesis takes place on the ribosome, where genetic information carried by messenger RNA is translated into a sequence of amino acids. This process is terminated when a stop codon moves into the ribosomal decoding centre (DC) and is recognized by a class-1 release factor (RF). RFs have a conserved GGQ amino-acid motif, which is crucial for peptide release and is believed to interact directly with the peptidyl-transferase centre (PTC) of the 50S ribosomal subunit. Another conserved motif of RFs (SPF in RF2) has been proposed to interact directly with stop codons in the DC of the 30S subunit. The distance between the DC and PTC is approximately 73 A. However, in the X-ray structure of RF2, SPF and GGQ are only 23 A apart, indicating that they cannot be at DC and PTC simultaneously. Here we show that RF2 is in an open conformation when bound to the ribosome, allowing GGQ to reach the PTC while still allowing SPF-stop-codon interaction. The results indicate new interpretations of accuracy in termination, and have implications for how the presence of a stop codon in the DC is signalled to PTC.

Binding Sites↗
PubMed1997

An introduction to the genetics of normal and defective hearing.

The recent rapid development of molecular biology techniques applied to the genetics of normal and defective hearing shed a new light on old questions regarding hearing and deafness. Genes are DNA sequences that determine characteristics, normally by specifying the sequence of aminoacids in a protein. The majority of genes is located in the chromosomes (human chromosomes have perhaps 80,000 pairs of genes). In addition there are 37 mithochondrial genes which are inherited only from the mother. One method used to identify candidate genes based on their function or pattern of tissue expression involves the construction of cDNA libraries from the target organ or tissue, in this case from the cochlea. The construction and characterization of cochlear cDNA libraries from humans and other species provide an important resource for rapid identification of cochlear genes involved in normal hearing and hearing disorders. Studies of the molecular genetics of the inner ear are hampered by the relative inaccessibility of the cochlea, by the limited number of cochlear and vestibular cells, and by our inability to maintain many of these cell types in long-term cultures. Several rodent inner-ear cDNA libraries and a human foetal cochlear cDNA library have already been constructed. Human and rodent cochlea-subtracted cDNA libraries are very useful for identifying genes controlling the development and maintenance of hearing. cDNA libraries constructed at different stages of development, and subtracted from each other, could be instrumental in identifying genes important at each stage of cochlear development. In addition, these libraries have the potential of fostering the identification of other proteins unique to the cochlea and will contribute to the identification, characterization, and functional analysis of these cochlea-specific proteins. Another important application of cDNA libraries is in identifying hearing-loss genes. Once the candidate gene for a given type of hearing loss is cloned and decoded, the structure of its protein product can be determined. This will provide insights into the biochemical function of the gene product in normal cochlear tissue, and will show why the genetic mutation results in hearing loss, that is, the recent identification of the myosin VIIa gene in Usher type IB. In addition, through the use of homologous recombination and transgenic technology, in vivo mouse models of inner-ear genetic disorders can be created. To date, 350 different genetic conditions associated with hearing impairment have been described, and during the past five years several of the genes involved in these form have already been mapped and identified.

Animals↗
PubMed2003

Multidimensional chemical genetic analysis of diversity-oriented synthesis-derived deacetylase inhibitors using cell-based assays.

Systematic chemical genetics aims to explore the space representing interactions between small molecules and biological systems. Beyond measuring binding interactions and enzyme inhibition, measuring changes in the activity of proteins in intact signaling networks is necessary. Toward this end, we are partitioning chemical space into regions with different biological activities using a panel of cell-based assays and small molecule "chemical genetic modifiers." Herein, we report on the use of this methodology for the discovery of 617 small molecule inhibitors of histone deacetylases from a multidimensional screen of an encoded, diversity-oriented synthesis library. Following decoding of chemical tags and resynthesis, we demonstrate the selectivity of one inhibitory molecule (tubacin) toward alpha-tubulin deacetylation and another (histacin) toward histone deacetylation. These small molecules will facilitate dissecting the role of acetylation in a variety of cell biological processes.

Acetylation↗
PubMed1987

Physiological levels of normal tRNA(CAGGln) can effect partial suppression of amber mutations in the yeast Saccharomyces cerevisiae.

A number of ciliated protozoa are known to read the stop codons UAA and UAG as sense codons that specify glutamine during protein synthesis. In considering evolutionary mechanisms for this curious divergence from the standard genetic code, we propose the existence of progenitor tRNAs for glutamine that can weakly suppress UAA and UAG codons. It has been previously shown that multicopy plasmids that overexpress normal tRNA(CAAGln) and tRNA(CAGGln) genes from the yeast Saccharomyces cerevisiae can partially suppress a number of yeast ochre and amber mutations, respectively. In the present study we show that the tRNA(CAGGln) gene can also function as a weak amber suppressor when expressed in cells at physiological levels. This observation is consistent with a role of tRNA(CAGGln) as an evolutionary progenitor of tRNAs that strongly decode UAG codons.

Animals↗
PubMed2003

Understanding complex signaling networks through models and metaphors.

Signaling networks are complex both in terms of the chemical and biophysical events that underlie them, and in the sheer number of interactions. Computer models are powerful tools to deal with both aspects of complexity, but their utility goes beyond simply replicating signaling events in silicon. Their great advantage is as a tool to understanding. The completeness of the description demanded by computer models highlights gaps in knowledge. The quantitative description in models facilitates a mapping between different kinds of analysis methods for complex systems. Systems analysis methods can highlight stable states of signaling networks and describe the transitions between them. Modeling also reveals functional similarities between signaling network properties and other well-understood systems such as electronic devices and neural networks. These suggest various metaphors as a tool to understanding. Based on such descriptions, it is possible to regard signaling networks as systems that decode complex inputs in time, space and chemistry into combinatorial output patterns of signaling activity. This would provide a natural interface to the combinatorial input patterns required by genetic circuits. Thus, a combination of computer modeling methods to capture the complexity and details, and useful abstractions revealed by these models, is necessary to achieve both rigorous description as well as human understanding.

Algorithms↗
PubMed2000

A ratchet-like inter-subunit reorganization of the ribosome during translocation.

The ribosome is a macromolecular assembly that is responsible for protein biosynthesis following genetic instructions in all organisms. It is composed of two unequal subunits: the smaller subunit binds messenger RNA and the anticodon end of transfer RNAs, and helps to decode the mRNA; and the larger subunit interacts with the amino-acid-carrying end of tRNAs and catalyses the formation of the peptide bonds. After peptide-bond formation, elongation factor G (EF-G) binds to the ribosome, triggering the translocation of peptidyl-tRNA from its aminoacyl site to the peptidyl site, and movement of mRNA by one codon. Here we analyse three-dimensional cryo-electron microscopy maps of the Escherichia coli 70S ribosome in various functional states, and show that both EF-G binding and subsequent GTP hydrolysis lead to ratchet-like rotations of the small 30S subunit relative to the large 50S subunit. Furthermore, our finding indicates a two-step mechanism of translocation: first, relative rotation of the subunits and opening of the mRNA channel following binding of GTP to EF-G; and second, advance of the mRNA/(tRNA)2 complex in the direction of the rotation of the 30S subunit, following GTP hydrolysis.

Biological Transport↗
PubMed1994

Unique structure of new serine tRNAs responsible for decoding leucine codon CUG in various Candida species and their putative ancestral tRNA genes.

In an asporogenic yeast, Candida cylindracea, codon CUG is not translated as leucine but as serine. On the basis of our recent work on the determination of the genetic code using in vitro translation systems coupled with isolation of the corresponding tRNA molecules, it appears that this non-universal genetic code is unitized not only in C cylindracea but also in various Hemiascomycetes. Here we show that in addition to the species already reported, three pathogenic yeasts, C guilliermondii, C lusitaniae and C tropicalis, have tRNA(Ser)CAG, indicating that this non-universal genetic code (CUG=Ser) also exists in these species. Determination of their primary structures revealed that the uridine conserved at position 33 in usual tRNAs, is replaced by guanosine or cytidine. This suggests that the three-dimensional structures of the anticodon loop of these tRNAs differ from the conventional structure comprising the U turn in this position. Moreover, we succeeded in isolating putative ancestral serine tRNA genes whose sequences are highly homologous to tRNA(Ser)CAG in each case. These tRNA genes all have the anticodon sequence CGA corresponding to the codon UCG, indicating that tRNA(Ser)CAG might have emerged from tRNA(Ser)CGA during evolutionary change of the assignment of codon CUG.

Base Sequence↗
PubMed2000

One protein from two open reading frames: mechanism of a 50 nt translational bypass.

Translating ribosomes bypass a 50 nt coding gap in order to fuse the information found in the two open reading frames (ORFs) of bacteriophage T4 gene 60. This study investigates the underlying mechanism by focusing on the competition between initiation of bypassing and termination at the end of the first ORF. While nearly all ribosomes initiate bypassing, no more than 50% resume translation in the second ORF. Two previously described cis-acting stimulatory signals are critical for favoring initiation of bypassing over termination. Genetic analysis of these signals supports a working model in which the first (a stem-loop structure at the junction between the first ORF and the coding gap) interferes with decoding in the A-site, and the second (a stretch of amino acids in the nascent peptide encoded by the first ORF) destabilizes peptidyl-tRNA-mRNA pairing.

Amino Acid Sequence↗