Biomedical subjects

January Weiner

Publications and source records attributed to January Weiner.

5 recordsLinked to original sources

PubMed2006

Evolution of circular permutations in multidomain proteins.

Modular rearrangements play an important role in protein evolution. Functional modules, often tantamount to structural domains or smaller fragments, are in many cases well conserved but reoccur in a different order and across many protein families. The underlying genetic mechanisms are gene duplication, fusion, and loss of sequence fragments. As a consequence, the sequential order of domains can be inverted, leading to what is known as circularly permutated proteins. Using a recently developed algorithm, we have identified a large number of such rearrangements and analyzed their evolutionary history. We searched for examples which have arisen by one of the three postulated mechanisms: independent fusion/fission, "duplication/deletion," and plasmid-mediated "cut and paste." We conclude that all three mechanisms can be observed, with the independent fusion/fission being the most frequent. This can be partly attributed to highly mobile domains. Duplication/deletion has been found in modular proteins such as peptide synthases.

Archaea↗

PubMed2006

Domain deletions and substitutions in the modular protein evolution.

The main mechanisms shaping the modular evolution of proteins are gene duplication, fusion and fission, recombination and loss of fragments. While a large body of research has focused on duplications and fusions, we concentrated, in this study, on how domains are lost. We investigated motif databases and introduced a measure of protein similarity that is based on domain arrangements. Proteins are represented as strings of domains and comparison was based on the classic dynamic alignment scheme. We found that domain losses and duplications were more frequent at the ends of proteins. We showed that losses can be explained by the introduction of start and stop codons which render the terminal domains nonfunctional, such that further shortening, until the whole domain is lost, is not evolutionarily selected against. We demonstrated that domains which also occur as single-domain proteins are less likely to be lost at the N terminus and in the middle, than at the C terminus. We conclude that fission/fusion events with single-domain proteins occur mostly at the C terminus. We found that domain substitutions are rare, in particular in the middle of proteins. We also showed that many cases of substitutions or losses result from erroneous annotations, but we were also able to find courses of evolutionary events where domains vanish over time. This is explained by a case study on the bacterial formate dehydrogenases.

Amino Acid Motifs↗

PubMed2005

Rapid motif-based prediction of circular permutations in multi-domain proteins.

MOTIVATION: Rearrangements of protein domains and motifs such as swaps and circular permutations (CPs) can produce erroneous results in searching sequence databases when using traditional methods based on linear sequence alignments. Circular permutations are also of biological relevance because they can help to better understand both protein evolution and functionality. RESULTS: We have developed an algorithm, RASPODOM, which is based on the classical recursive alignment scheme. Sequences are represented as strings of domains taken from precompiled resources of domain (motif) databases such as ProDom. The algorithm works several orders of magnitude faster than a reimplementation of the existing CP detection algorithm working on strings of amino acids, produces virtually no false positives and allows the discrimination of true CPs from 'intermediate' CPs (iCPs). Several true CPs which have not been reported in literature so far could be identified from Swiss-Prot/TrEMBL within minutes.

Algorithms↗

PubMed2005

Phylogenetic profiling of protein interaction networks in eukaryotic transcription factors reveals focal proteins being ancestral to hubs.

The combination of genomic, proteomic and other data, enables to reconstruct the evolution of complex cellular units thus transcending the more reductionistic view of traditional molecular phylogeny. However, most models which try to investigate the evolution of protein interaction networks so far are based on the analysis of their global statistical properties, such as their scale-free behaviour. We have investigated phylogenies of three families of ancient eukaryotic transcription factors for which fairly reliable interaction data are available. For all three families, bZIP, bHLH and NR (nuclear receptors), we find that homo-dimerising proteins were probably the ancestors and that series of single gene duplications, in combination with domain-rearrangements, were the main driving force in establishing the basic network architecture. However, the overall scaling behaviour does not always precisely confer to some theoretical models on network evolution. In conclusion, new models which reflect the biological details of molecular evolution, need to be developed.

Basic-Leucine Zipper Transcription Factors↗

PubMed2004

Cross-complementation between the products of the genes P1 and ORF6 of Mycoplasma pneumoniae subtypes 1 and 2.

The genes P1 (MPN141) and ORF6 (MPN142) are essential for the successful colonization of the human respiratory tract by Mycoplasma pneumoniae. Both genes are located in the P1 operon, which consists of three genes. The P1 gene is the second gene in the operon, followed by the ORF6 gene. The P1 gene contains two (RepMP2/3, RepMP4) and the ORF6 gene one (RepMP5) specific repetitive DNA sequence, of which seven to nine similar but not identical copies are dispersed on the genome. Despite this large potential pool for genetic variation, M. pneumoniae isolates from patients contain only one of two distinct combinations of the genes P1 and ORF6. To analyse the functions of the repetitive DNA sequences, two 'new' combinations of the genes P1 and ORF6 were constructed, keeping the P1 gene constant but exchanging RepMP5 copies of the ORF6 gene. M. pneumoniae was transformed with these constructs and the transformants were tested for their ability to grow and survive under in vitro conditions and in guinea pigs. The two transformants colonized the respiratory tract of guinea pigs and showed no obvious differences in their growth behaviour compared to M. pneumoniae isolates from patients. The results indicate that the subtype-specific combinations of the repetitive elements in the P1 and ORF6 genes are not essential for the successful adherence of M. pneumoniae to host cells and the colonization of the respiratory tract of guinea pigs.

Adhesins, Bacterial↗