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Search Results: 1 - 10 of 208669 matches for " L Aravind "
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Opening Pandora's Box: making biological discoveries through computational data exploration
L Aravind
Biology Direct , 2007, DOI: 10.1186/1745-6150-2-29
Abstract: The essential philosophy of this new movement within biology – computational biology – has been the use of computational methods to explore repositories of biological information to make new scientific discoveries. An early example of the success of these methods was the identification of the helix-turn-helix domain as a determinant of DNA-protein interaction [1]. This allowed the prediction of diverse bacterial and eukaryotic transcription factors, and resulted in testable hypotheses regarding the functions of key developmental regulators and oncogenes [2,3]. Ever since, computational investigations have resulted in discovery of new protein domains and prediction of their biochemical roles [4], discovery of new RNAs [5], identification of subcellular targeting signals in proteins [6] and prediction of transcription factor binding sites [7]. Application of such methodologies has also been at the heart of genomics – being central to the interpretation of genome sequences. Most remarkably it has allowed us to reconstruct the biology of diverse life forms, such as the syphilis pathogen [8], the malarial parasite [9] or the diverse uncultivable microorganisms [10], which were never too amenable to classical experimentation. The successes of genomics have also spawned whole assemblies of new forms of high-throughput data. These include genome-scale collations of data pertaining to gene expression, protein-protein interactions, genetic interactions and intra-population genomic polymorphisms. By adding a new layer of contextual information to that contained in sequences and structures of biomolecules these new datasets greatly add to the power of the computational discovery process.The principal idea behind announcing the Discovery Notes section of Biology Direct is to augment the process of discovery in light of the unprecedented accumulation of biological data. The articles submitted to this section aim to occupy a specific niche in the already rich menagerie of publicat
Gene flow and biological conflict systems in the origin and evolution of eukaryotes
L. Aravind
Frontiers in Cellular and Infection Microbiology , 2012, DOI: 10.3389/fcimb.2012.00089
Abstract: The endosymbiotic origin of eukaryotes brought together two disparate genomes in the cell. Additionally, eukaryotic natural history has included other endosymbiotic events, phagotrophic consumption of organisms, and intimate interactions with viruses and endoparasites. These phenomena facilitated large-scale lateral gene transfer and biological conflicts. We synthesize information from nearly two decades of genomics to illustrate how the interplay between lateral gene transfer and biological conflicts has impacted the emergence of new adaptations in eukaryotes. Using apicomplexans as example, we illustrate how lateral transfer from animals has contributed to unique parasite-host interfaces comprised of adhesion- and O-linked glycosylation-related domains. Adaptations, emerging due to intense selection for diversity in the molecular participants in organismal and genomic conflicts, being dispersed by lateral transfer, were subsequently exapted for eukaryote-specific innovations. We illustrate this using examples relating to eukaryotic chromatin, RNAi and RNA-processing systems, signaling pathways, apoptosis and immunity. We highlight the major contributions from catalytic domains of bacterial toxin systems to the origin of signaling enzymes (e.g., ADP-ribosylation and small molecule messenger synthesis), mutagenic enzymes for immune receptor diversification and RNA-processing. Similarly, we discuss contributions of bacterial antibiotic/siderophore synthesis systems and intra-genomic and intra-cellular selfish elements (e.g., restriction-modification, mobile elements and lysogenic phages) in the emergence of chromatin remodeling/modifying enzymes and RNA-based regulation. We develop the concept that biological conflict systems served as evolutionary “nurseries” for innovations in the protein world, which were delivered to eukaryotes via lateral gene flow to spur key evolutionary innovations all the way from nucleogenesis to lineage-specific adaptations.
Evolutionary history, structural features and biochemical diversity of the NlpC/P60 superfamily of enzymes
Vivek Anantharaman, L Aravind
Genome Biology , 2003, DOI: 10.1186/gb-2003-4-2-r11
Abstract: Detailed analysis of the N1pC/P60 peptidases showed that these proteins define a large superfamily encompassing several diverse groups of proteins. In addition to the well characterized P60-like proteins, this superfamily includes the AcmB/LytN and YaeF/YiiX families of bacterial proteins, the amidase domain of bacterial and kinetoplastid glutathionylspermidine synthases (GSPSs), and several proteins from eukaryotes, phages, poxviruses, positive-strand RNA viruses, and certain archaea. The eukaryotic members include lecithin retinol acyltransferase (LRAT), nematode developmental regulator Egl-26, and candidate tumor suppressor H-rev107. These eukaryotic proteins, along with the bacterial YaeF/poxviral G6R family, show a circular permutation of the catalytic domain. We identified three conserved residues, namely a cysteine, a histidine and a polar residue, that are involved in the catalytic activities of this superfamily. Evolutionary analysis of this superfamily shows that it comprises four major families, with diverse domain architectures in each of them.Several related, but distinct, catalytic activities, such as murein degradation, acyl transfer and amide hydrolysis, have emerged in the N1pC/P60 superfamily. The three conserved catalytic residues of this superfamily are shown to be equivalent to the catalytic triad of the papain-like thiol peptidases. The predicted structural features indicate that the N1pC/P60 enzymes contain a fold similar to the papain-like peptidases, transglutaminases and arylamine acetyltransferases.The rigid cell wall that forms a protective layer around most bacterial cells is chiefly composed of peptidoglycan, a biopolymer unique to bacteria [1,2]. The backbone of peptidoglycan consists of a chain of alternating N-acetylglucosamine (NAG) and N-acetylmuramate (NAM) units linked by a 1-4 glycosidic bond between the two hexoses. The NAM units of the glycan chain are linked to short peptides, which are synthesized via a ribosome-independent
New connections in the prokaryotic toxin-antitoxin network: relationship with the eukaryotic nonsense-mediated RNA decay system
Vivek Anantharaman, L Aravind
Genome Biology , 2003, DOI: 10.1186/gb-2003-4-12-r81
Abstract: Using sequence profile analysis we were able unify the RelE- and ParE-type toxins with several families of small, uncharacterized proteins from diverse bacteria and archaea into a single superfamily. Gene neighborhood analysis showed that the majority of these proteins were encoded by genes in characteristic neighborhoods, in which genes encoding toxins always co-occurred with genes encoding transcription factors that are also antitoxins. The transcription factors accompanying the RelE/ParE superfamily may belong to unrelated or distantly related superfamilies, however. We used this conserved neighborhood template to transitively search genomes and identify novel post-segregational cell killing-related systems. One of these novel systems, observed in several prokaryotes, contained a predicted toxin with a PilT-N terminal (PIN) domain, which is also found in proteins of the eukaryotic nonsense-mediated RNA decay system. These searches also identified novel transcription factors (antitoxins) in post-segregational cell killing systems. Furthermore, the toxin Doc defines a potential metalloenzyme superfamily, with novel representatives in bacteria, archaea and eukaryotes, that probably acts on nucleic acids.The tightly maintained gene neighborhoods of post-segregational cell killing-related systems appear to have evolved by in situ displacement of genes for toxins or antitoxins by functionally equivalent but evolutionarily unrelated genes. We predict that the novel post-segregational cell killing-related systems containing a PilT-N terminal domain toxin and the eukaryotic nonsense-mediated RNA decay system are likely to function via a common mechanism, in which the PilT-N terminal domain cleaves ribosome-associated transcripts. The core of the eukaryotic nonsense-mediated RNA decay system has probably evolved from a post-segregational cell killing-related system.Post-segregational cell killing (PSK) is a widespread mechanism that aids several plasmids to maintain themse
The PRC-barrel: a widespread, conserved domain shared by photosynthetic reaction center subunits and proteins of RNA metabolism
Vivek Anantharaman, L Aravind
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-11-research0061
Abstract: We show that the PRC-H β-barrel domain is the prototype of a novel superfamily of protein domains, the PRC-barrels, approximately 80 residues long, which is widely represented in bacteria, archaea and plants. This domain is also present at the carboxyl terminus of the pan-bacterial protein RimM, which is involved in ribosomal maturation and processing of 16S rRNA. A family of small proteins conserved in all known euryarchaea are composed entirely of a single stand-alone copy of the domain. Versions of this domain from photosynthetic proteobacteria contain a conserved acidic residue that is thought to regulate the reduction of quinones in the light-induced electron-transfer reaction. Closely related forms containing this acidic residue are also found in several non-photosynthetic bacteria, as well as in cyanobacteria, which have reaction centers with a different organization. We also show that the domain contains several determinants that could mediate specific protein-protein interactions.The PRC-barrel is a widespread, ancient domain that appears to have been recruited to a variety of biological systems, ranging from RNA processing to photosynthesis. Identification of this versatile domain in numerous proteins could aid investigation of unexplored aspects of their biology.Identification of conserved protein domains that span a wide range of biological functions provide deep insights regarding the origin and evolution of complex biological systems, These versatile conserved domains often have catalytic or structural roles that can be utilized, with small variations, in different contexts. The P-loop-containing nucleotide phosphatase fold represents one such catalytic domain that is utilized in almost every conceivable biological system in all the three superkingdoms of life [1,2]. Folds such as the SH3-like barrels, the PAS-like fold, the OB fold, the double-stranded β-helix, the β-propeller and rubredoxin-like zinc ribbons are predominantly non-catalytic domains th
The GOLD domain, a novel protein module involved in Golgi function and secretion
Vivek Anantharaman, L Aravind
Genome Biology , 2002, DOI: 10.1186/gb-2002-3-5-research0023
Abstract: Using sensitive sequence-profile analysis methods, we identified a novel β-strand-rich domain, the GOLD (Golgi dynamics) domain, in the p24 proteins and several other proteins with roles in Golgi dynamics and secretion. This domain is predicted to mediate diverse protein-protein interactions. Other than in the p24 proteins, the GOLD domain is always found combined with lipid- or membrane-association domains such as the pleckstrin homology (PH), Sec14p and FYVE domains.The identification of the GOLD domain could aid in directed investigation of the role of the p24 proteins in the secretion process. The newly detected group of GOLD-domain proteins, which might simultaneously bind membranes and other proteins, point to the existence of a novel class of adaptors that could have a role in the assembly of membrane-associated complexes or in regulating assembly of cargo into membranous vesicles.The Golgi complex is the central secretory organelle of most eukaryotic cells and consists of membranous stacks called cisternae [1,2]. Secreted proteins, like all other proteins, are synthesized in the endoplasmic reticulum (ER) and are specifically packaged into vesicles that bud off from the ER in a GTP-dependent process [3,4]. These lipid vesicles are coated with the COPII coat protein-complex and are equipped with the ATP-dependent vesicle-fusion apparatus. They carry the secretory cargo to the cis surface of the Golgi complex, with which they fuse, delivering the cargo. A second type of vesicle, coated by the COPI coat-protein complex, is part of a retrograde pathway that buds off the Golgi membrane and returns proteins that are not targeted for secretion back to the endoplasm [3,4].Studies on the secretory system in crown-group eukaryotes (plants, animals and fungi) have uncovered a family of proteins, the p24 (p24/gp25L/emp24/Erp) family, that have an important role in cargo selection and packaging into COPII-coated vesicles [5,6,7,8]. Additionally, they might also function
Novel eukaryotic enzymes modifying cell-surface biopolymers
Vivek Anantharaman, L Aravind
Biology Direct , 2010, DOI: 10.1186/1745-6150-5-1
Abstract: Using sequence analysis and conservation we define the acyltransferase domain prototyped by the fungal Cas1p proteins, identify its active site residues and unify them to the superfamily of classical 10TM acyltransferases (e.g. oatA). We also identify a novel family of esterases (prototyped by the previously uncharacterized N-terminal domain of Cas1p) that have a similar fold as the SGNH/GDSL esterases but differ from them in their conservation pattern.We posit that the combined action of the acyltransferase and esterase domain plays an important role in controlling the acylation levels of glycans and thereby regulates their physico-chemical properties such as hygroscopicity, resistance to enzymatic hydrolysis and physical strength. We present evidence that the action of these novel enzymes on glycans might play an important role in host-pathogen interaction of plants, fungi and metazoans. We present evidence that in plants (e.g. PMR5 and ESK1) the regulation of carbohydrate acylation by these acylesterases might also play an important role in regulation of transpiration and stress resistance. We also identify a subfamily of these esterases in metazoans (e.g. C7orf58), which are fused to an ATP-grasp amino acid ligase domain that is predicted to catalyze, in certain animals, modification of cell surface polymers by amino acid or peptides.This article was reviewed by Gaspar Jekely and Frank EisenhaberEukaryotes display a rich complement of secreted and membrane-anchored cell-surface proteins, whose amino acid side-chains are subject to numerous post-translational modifications. These modifications include addition of extensive polysaccharide moieties to asparagine or serine/threonine side chains (N and O linked glycosylation respectively), sulfatation, hydroxylation and cross-linking. These modified surface proteins, together with other biopolymers such as polysaccharides, which might also be highly modified and cross-linked, constitute diverse organic matrices of eu
Application of comparative genomics in the identification and analysis of novel families of membrane-associated receptors in bacteria
Vivek Anantharaman, L Aravind
BMC Genomics , 2003, DOI: 10.1186/1471-2164-4-34
Abstract: Utilizing the currently available wealth of prokaryotic genomic sequences, we set up a computational screen to identify putative 7 (TM) and other multi-pass membrane receptors in prokaryotes. As a result of this procedure we were able to recover two widespread families of 7 TM receptors in bacteria that are distantly related to the eukaryotic 7 TM receptors and prokaryotic rhodopsins. Using sequence profile analysis, we were able to establish that the first members of these receptor families contain one of two distinct N-terminal extracellular globular domains, which are predicted to bind ligands such as carbohydrates. In their intracellular portions they contain fusions to a variety of signaling domains, which suggest that they are likely to transduce signals via cyclic AMP, cyclic diguanylate, histidine phosphorylation, dephosphorylation, and through direct interactions with DNA. The second family of bacterial 7 TM receptors possesses an α-helical extracellular domain, and is predicted to transduce a signal via an intracellular HD hydrolase domain. Based on comparative analysis of gene neighborhoods, this receptor is predicted to function as a regulator of the diacylglycerol-kinase-dependent glycerolipid pathway. Additionally, our procedure also recovered other types of putative prokaryotic multi-pass membrane associated receptor domains. Of these, we characterized two widespread, evolutionarily mobile multi-TM domains that are fused to a variety of C-terminal intracellular signaling domains. One of these typified by the Gram-positive LytS protein is predicted to be a potential sensor of murein derivatives, whereas the other one typified by the Escherichia coli UhpB protein is predicted to function as sensor of conformational changes occurring in associated membrane proteinsWe present evidence for considerable variety in the types of uncharacterized surface receptors in bacteria, and reconstruct the evolutionary processes that model their diversity. The identifica
Novel conserved domains in proteins with predicted roles in eukaryotic cell-cycle regulation, decapping and RNA stability
Vivek Anantharaman, L Aravind
BMC Genomics , 2004, DOI: 10.1186/1471-2164-5-45
Abstract: Using sensitive sequence profile searches, homology-based fold recognition and sequence-structure superpositions, we identified novel, divergent versions of the Sm domain in the Scd6p family of proteins. This family of Sm-related domains shares certain features of conventional Sm domains, which are required for binding RNA, in addition to possessing some unique conserved features. We also show that these proteins contain a second previously uncharacterized C-terminal domain, termed the FDF domain (after a conserved sequence motif in this domain). The FDF domain is also found in the fungal Dcp3p-like and the animal FLJ22128-like proteins, where it fused to a C-terminal domain of the YjeF-N domain family. In addition to the FDF domains, the FLJ22128-like proteins contain yet another divergent version of the Sm domain at their extreme N-terminus. We show that the YjeF-N domains represent a novel version of the Rossmann fold that has acquired a set of catalytic residues and structural features that distinguish them from the conventional dehydrogenases.Several lines of contextual information suggest that the Scd6p family and the Dcp3p-like proteins are conserved components of the eukaryotic RNA metabolism system. We propose that the novel domains reported here, namely the divergent versions of the Sm domain and the FDF domain may mediate specific RNA-protein and protein-protein interactions in cytoplasmic ribonucleoprotein complexes. More specifically, the protein complexes containing Sm-like domains of the Scd6p family are predicted to regulate the stability of mRNA encoding proteins involved in cell cycle progression and vesicular assembly. The Dcp3p and FLJ22128 proteins may localize to the cytoplasmic processing bodies and possibly catalyze a specific processing step in the decapping pathway. The explosive diversification of Sm domains appears to have played a role in the emergence of several uniquely eukaryotic ribonucleoprotein complexes, including those involved i
Application of comparative genomics in the identification and analysis of novel families of membrane-associated receptors in bacteria
Anantharaman Vivek,Aravind L
BMC Genomics , 2003,
Abstract: Background A great diversity of multi-pass membrane receptors, typically with 7 transmembrane (TM) helices, is observed in the eukaryote crown group. So far, they are relatively rare in the prokaryotes, and are restricted to the well-characterized sensory rhodopsins of various phototropic prokaryotes. Results Utilizing the currently available wealth of prokaryotic genomic sequences, we set up a computational screen to identify putative 7 (TM) and other multi-pass membrane receptors in prokaryotes. As a result of this procedure we were able to recover two widespread families of 7 TM receptors in bacteria that are distantly related to the eukaryotic 7 TM receptors and prokaryotic rhodopsins. Using sequence profile analysis, we were able to establish that the first members of these receptor families contain one of two distinct N-terminal extracellular globular domains, which are predicted to bind ligands such as carbohydrates. In their intracellular portions they contain fusions to a variety of signaling domains, which suggest that they are likely to transduce signals via cyclic AMP, cyclic diguanylate, histidine phosphorylation, dephosphorylation, and through direct interactions with DNA. The second family of bacterial 7 TM receptors possesses an α-helical extracellular domain, and is predicted to transduce a signal via an intracellular HD hydrolase domain. Based on comparative analysis of gene neighborhoods, this receptor is predicted to function as a regulator of the diacylglycerol-kinase-dependent glycerolipid pathway. Additionally, our procedure also recovered other types of putative prokaryotic multi-pass membrane associated receptor domains. Of these, we characterized two widespread, evolutionarily mobile multi-TM domains that are fused to a variety of C-terminal intracellular signaling domains. One of these typified by the Gram-positive LytS protein is predicted to be a potential sensor of murein derivatives, whereas the other one typified by the Escherichia coli UhpB protein is predicted to function as sensor of conformational changes occurring in associated membrane proteins Conclusions We present evidence for considerable variety in the types of uncharacterized surface receptors in bacteria, and reconstruct the evolutionary processes that model their diversity. The identification of novel receptor families in prokaryotes is likely to aid in the experimental analysis of signal transduction and environmental responses of several bacteria, including pathogens such as Leptospira, Treponema, Corynebacterium, Coxiella, Bacillus anthracis and
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