1. |
- Joannin, Nicolas, et al.
(author)
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RSpred, a set of Hidden Markov Models to detect and classify the RIFIN and STEVOR proteins of Plasmodium falciparum
- 2011
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In: BMC Genomics. - : BioMed Central. - 1471-2164. ; 12:119
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Journal article (peer-reviewed)abstract
- Background: Many parasites use multicopy protein families to avoid their hosts immune system through a strategy called antigenic variation. RIFIN and STEVOR proteins are variable surface antigens uniquely found in the malaria parasites Plasmodium falciparum and P. reichenowi. Although these two protein families are different, they have more similarity to each other than to any other proteins described to date. As a result, they have been grouped together in one Pfam domain. However, a recent study has described the sub-division of the RIFIN protein family into several functionally distinct groups. These sub-groups require phylogenetic analysis to sort out, which is not practical for large-scale projects, such as the sequencing of patient isolates and meta-genomic analysis. Results: We have manually curated the rif and stevor gene repertoires of two Plasmodium falciparum genomes, isolates DD2 and HB3. We have identified 25% of mis-annotated and similar to 30 missing rif and stevor genes. Using these data sets, as well as sequences from the well curated reference genome (isolate 3D7) and field isolate data from Uniprot, we have developed a tool named RSpred. The tool, based on a set of hidden Markov models and an evaluation program, automatically identifies STEVOR and RIFIN sequences as well as the sub-groups: A-RIFIN, B-RIFIN, B1-RIFIN and B2-RIFIN. In addition to these groups, we distinguish a small subset of STEVOR proteins that we named STEVOR-like, as they either differ remarkably from typical STEVOR proteins or are too fragmented to reach a high enough score. When compared to Pfam and TIGRFAMs, RSpred proves to be a more robust and more sensitive method. We have applied RSpred to the proteomes of several P. falciparum strains, P. reichenowi, P. vivax, P. knowlesi and the rodent malaria species. All groups were found in the P. falciparum strains, and also in the P. reichenowi parasite, whereas none were predicted in the other species. Conclusions: We have generated a tool for the sorting of RIFIN and STEVOR proteins, large antigenic variant protein groups, into homogeneous sub-families. Assigning functions to such protein families requires their subdivision into meaningful groups such as we have shown for the RIFIN protein family. RSpred removes the need for complicated and time consuming phylogenetic analysis methods. It will benefit both research groups sequencing whole genomes as well as others working with field isolates. RSpred is freely accessible via http://www.ifm.liu.se/bioinfo/.
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2. |
- Jornvall, Hans, et al.
(author)
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Origin and evolution of medium chain alcohol dehydrogenases
- 2013
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In: Chemico-Biological Interactions. - : Elsevier. - 0009-2797 .- 1872-7786. ; 202:1-3, s. 91-96
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Journal article (peer-reviewed)abstract
- Different lines of alcohol dehydrogenases (ADHs) have separate superfamily origins, already recognized but now extended and re-evaluated by re-screening of the latest databank update. The short-chain form (SDR) is still the superfamily with most abundant occurrence, most multiple divergence, most prokaryotic emphasis, and most non-complicated architecture. This pattern is compatible with an early appearance at the time of the emergence of prokaryotic cellular life. The medium-chain form (MDR) is also old but second in terms of all the parameters above, and therefore compatible with a second emergence. However, this step appears seemingly earlier than previously considered, and may indicate sub-stages of early emergences at the increased resolution available from the now greater number of data entries. The Zn-MDR origin constitutes a third stage, possibly compatible with the transition to oxidative conditions on earth. Within all these three lines, repeated enzymogeneses gave the present divergence. MDR-ADH origin(s), at a fourth stage, may also be further resolved in multiple or extended modes, but the classical liver MDR-ADH of the liver type can still be traced to a gene duplication similar to 550 MYA (million years ago), at the early vertebrate radiation, compatible with the post-eon-shift, "Cambrian explosion". Classes and isozymes correspond to subsequent and recent duplicatory events, respectively. They illustrate a peculiar pattern with functional and emerging evolutionary distinctions between parent and emerging lines, suggesting a parallelism between duplicatory and mutational events, now also visible at separate sub-stages. Combined, all forms show distinctive patterns at different levels and illustrate correlations with global events. They further show that simple molecular observations on patterns, multiplicities and occurrence give much information, suggesting common divergence rules not much disturbed by horizontal gene transfers after the initial origins.
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3. |
- Kallberg, Yvonne
(author)
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Bioinformatic methods in protein characterization
- 2002
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Doctoral thesis (other academic/artistic)abstract
- Bioinformatics is an emerging interdisciplinary research field in which mathematics. computer science and biology meet. In this thesis. bioinformatic methods for analysis of functional and structural properties among proteins will be presented. I have developed and applied bioinformatic methods on the enzyme superfamily of short-chain dehydrogenases/reductases (SDRs), coenzyme-binding enzymes of the Rossmann fold type, and amyloid-forming proteins and peptides. The basis for bioinformatics is the availability of biological data, collected in different types of database. A non-redundant protein sequence database, KIND, has been compiled using a modification of the naïve algorithm. The database consists of the non- redundant union of the two protein sequence databases SWISSPROT and PIR, and the two databases derived from open reading frames TrEMBL and Genpept. By applying sequence comparison techniques in the form of multiple and pair-wise alignment methods, protein sequences from known complete genomes have been compared and SDR members have been identified. Inter-species comparisons reveal eight protein clusters in common to human, animal and plant genomes. The SDR superfamily, previously divided into only two families, is now found to consist of Five families. Using a combination of hidden Markov models and motifs, an extendable assignment scheme has been developed, including a subfamily division of the two largest families, based on coenzyme specificity. This scheme will be a valuable tool in functional and structural assignments of novel SDR members. Coenzyme specificity has also been addressed in a more general sense, where a coenzyme prediction method has been developed. The method is based on the existence of specific sequence motifs, characteristic of coenzyme binding. Given an amino acid sequence, identification of coenzyme-binding regions can be done with over 90% success rate, but prediction of coenzyme type still needs to be improved. A method to predict amyloid fibril-forming proteins has been developed, utilizing unsuccessful secondary structure predictions of regions with weak a-helical propensities. Experimentally determined a-helices were compared with their predicted secondary structures. in a large set of proteins. Among these, it was found that proteins with amyloid fibril-forming tendencies harbours a-helices that are falsely predicted to be beta-strands, suggesting that this type of proteins have segments with ail amino acid composition typical of beta-strands rather than a-helices. This phenomenon, now referred to as discordance, probably is one of the reasons why some proteins fail to fold properly. and instead form insoluble fibrils that, directly or indirectly, are the cause of severe diseases such as Alzheimer's disease and the prion diseases. In conclusion. this thesis shows that bioinformatic methods, applied to protein sequence data, are important tools to study and characterize structural and functional properties among proteins.
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4. |
- Kallberg, Yvonne, et al.
(author)
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Classification of the short-chain dehydrogenase/reductase superfamily using hidden Markov models
- 2010
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In: FEBS JOURNAL. - : Blackwell Publishing Ltd. - 1742-464X .- 1742-4658. ; 277:10, s. 2375-2386
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Journal article (peer-reviewed)abstract
- The short-chain dehydrogenase/reductase (SDR) superfamily now has over 47 000 members, most of which are distantly related, with typically 20-30% residue identity in pairwise comparisons, making it difficult to obtain an overview of this superfamily. We have therefore developed a family classification system, based upon hidden Markov models (HMMs). To this end, we have identified 314 SDR families, encompassing about 31 900 members. In addition, about 9700 SDR forms belong to families with too few members at present to establish valid HMMs. In the human genome, we find 47 SDR families, corresponding to 82 genes. Thirteen families are present in all three domains (Eukaryota, Bacteria, and Archaea), and are hence expected to catalyze fundamental metabolic processes. The majority of these enzymes are of the extended type, in agreement with earlier findings. About half of the SDR families are only found among bacteria, where the classical SDR type is most prominent. The HMM-based classification is used as a basis for a sustainable and expandable nomenclature system.
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5. |
- Kallberg, Yvonne, et al.
(author)
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Evolutionary Conservation of the Ribosomal Biogenesis Factor Rbm19/Mrd1 : Implications for Function
- 2012
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9
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Journal article (peer-reviewed)abstract
- Ribosome biogenesis in eukaryotes requires coordinated folding and assembly of a pre-rRNA into sequential pre-rRNA-protein complexes in which chemical modifications and RNA cleavages occur. These processes require many small nucleolar RNAs (snoRNAs) and proteins. Rbm19/Mrd1 is one such protein that is built from multiple RNA-binding domains (RBDs). We find that Rbm19/Mrd1 with five RBDs is present in all branches of the eukaryotic phylogenetic tree, except in animals and Choanoflagellates, that instead have a version with six RBDs and Microsporidia which have a minimal Rbm19/Mrd1 protein with four RBDs. Rbm19/Mrd1 therefore evolved as a multi-RBD protein very early in eukaryotes. The linkers between the RBDs have conserved properties; they are disordered, except for linker 3, and position the RBDs at conserved relative distances from each other. All but one of the RBDs have conserved properties for RNA-binding and each RBD has a specific consensus sequence and a conserved position in the protein, suggesting a functionally important modular design. The patterns of evolutionary conservation provide information for experimental analyses of the function of Rbm19/Mrd1. In vivo mutational analysis confirmed that a highly conserved loop 5-beta 4-strand in RBD6 is essential for function.
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6. |
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7. |
- Moummou, Hanane, et al.
(author)
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The Plant Short-Chain Dehydrogenase (SDR) superfamily: genome-wide inventory and diversification patterns
- 2012
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In: BMC Plant Biology. - : BioMed Central. - 1471-2229. ; 12:219
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Journal article (peer-reviewed)abstract
- Background: Short-chain dehydrogenases/reductases (SDRs) form one of the largest and oldest NAD(P)(H) dependent oxidoreductase families. Despite a conserved Rossmann-fold structure, members of the SDR superfamily exhibit low sequence similarities, which constituted a bottleneck in terms of identification. Recent classification methods, relying on hidden-Markov models (HMMs), improved identification and enabled the construction of a nomenclature. However, functional annotations of plant SDRs remain scarce. less thanbrgreater than less thanbrgreater thanResults: Wide-scale analyses were performed on ten plant genomes. The combination of hidden Markov model (HMM) based analyses and similarity searches led to the construction of an exhaustive inventory of plant SDR. With 68 to 315 members found in each analysed genome, the inventory confirmed the over-representation of SDRs in plants compared to animals, fungi and prokaryotes. The plant SDRs were first classified into three major types - classical, extended and divergent - but a minority (10% of the predicted SDRs) could not be classified into these general types (unknown or atypical types). In a second step, we could categorize the vast majority of land plant SDRs into a set of 49 families. Out of these 49 families, 35 appeared early during evolution since they are commonly found through all the Green Lineage. Yet, some SDR families - tropinone reductase-like proteins (SDR65C), ABA2-like-NAD dehydrogenase (SDR110C), salutaridine/menthone-reductase-like proteins (SDR114C), dihydroflavonol 4-reductase-like proteins (SDR108E) and isoflavone-reductase-like (SDR460A) proteins - have undergone significant functional diversification within vascular plants since they diverged from Bryophytes. Interestingly, these diversified families are either involved in the secondary metabolism routes (terpenoids, alkaloids, phenolics) or participate in developmental processes (hormone biosynthesis or catabolism, flower development), in opposition to SDR families involved in primary metabolism which are poorly diversified. less thanbrgreater than less thanbrgreater thanConclusion: The application of HMMs to plant genomes enabled us to identify 49 families that encompass all Angiosperms (higher plants) SDRs, each family being sufficiently conserved to enable simpler analyses based only on overall sequence similarity. The multiplicity of SDRs in plant kingdom is mainly explained by the diversification of large families involved in different secondary metabolism pathways, suggesting that the chemical diversification that accompanied the emergence of vascular plants acted as a driving force for SDR evolution.
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8. |
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9. |
- Persson, Bengt, et al.
(author)
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Classification and nomenclature of the superfamily of short-chain dehydrogenases/reductases (SDRs)
- 2013
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In: Chemico-Biological Interactions. - : ELSEVIER IRELAND LTD, ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND. - 0009-2797 .- 1872-7786. ; 202:1-3, s. 111-115
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Journal article (peer-reviewed)abstract
- The short-chain dehydrogenases/reductases (SDRs) constitute one of the largest protein superfamilies known today. The members are distantly related with typically 20-30% residue identity in pair-wise comparisons. Still, all hitherto structurally known SDRs present a common three-dimensional structure consisting of a Rossmann fold with a parallel beta sheet flanked by three helices on each side. Using hidden Markov models (HMMs), we have developed a semi-automated subclassification system for this huge family. Currently, 75% of all SDR forms have been assigned to one of the 464 families totalling 122,940 proteins. There are 47 human SDR families, corresponding to 75 genes. Most human SDR families (35 families) have only one gene, while 12 have between 2 and 8 genes. For more than half of the human SDR families, the three-dimensional fold is known. The number of SDR members increases considerably every year, but the number of SDR families now starts to converge. The classification method has paved the ground for a sustainable and expandable nomenclature system. Information on the SDR superfamily is continuously updated at http://sdr-enzymes.org/.
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10. |
- Persson, Bengt, et al.
(author)
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The SDR (short-chain dehydrogenase/reductase and related enzymes) nomenclature initiative
- 2009
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In: Chemico-Biological Interactions. - : Elsevier BV. - 0009-2797 .- 1872-7786. ; 178:1-3, s. 94-98
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Journal article (peer-reviewed)abstract
- Short-chain dehydrogenases/reductases (SDR) constitute one of the largest enzyme superfamilies with presently over 46,000 members. In phylogenetic comparisons, members of this superfamily show early divergence where the majority have only low pairwise sequence identity, although sharing common structural properties. The SDR enzymes are present in virtually all genomes investigated, and in humans over 70 SDR genes have been identified. In humans, these enzymes are involved in the metabolism of a large variety of compounds, including steroid hormones, prostaglandins, retinoids, lipids and xenobiotics. It is now clear that SDRs represent one of the oldest protein families and contribute to essential functions and interactions of all forms of life. As this field continues to grow rapidly, a systematic nomenclature is essential for future annotation and reference purposes. A functional subdivision of the SDR superfamily into at least 200 SDR families based upon hidden Markov models forms a suitable foundation for such a nomenclature system, which we present in this paper using human SDRs as examples.
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