Dr. Aravind has an ongoing interest in using computational methods to decipher various aspects of protein structure, function and evolution. During 2013, Dr. Aravind demonstrated exceptional progress and effective planning and execution of several major research projects along these lines. These research projects cover the areas of molecular enzymology, signal transduction and transcriptional regulation mechanisms using computational methods. His group comprising of 2 staff scientist, 2 post-doctoral fellows and one contractor has over 10 publications in peer-reviewed publications in top scientific journals. He also published a comprehensive monograph on signal sensor domains in bacteria, which is recognized as a major work in this field. In this period, Dr. Aravind was also consulted to serve as a referee for several manuscripts submitted to the journals Science, Cell, Genome Research, Nature, and Nucleic Acids Research, Biology Direct. He was an invited to speaker at three venues in course of the year. Some highlights of Dr. Aravind's 2013 research program include the following: Dr. Aravind and his group made discoveries leading to an improved understanding of the origin of cilia and their functions. In addition to their role in motility, eukaryotic cilia serve as a distinct compartment for signal transduction and regulatory sequestration of biomolecules. Recent genetic and biochemical studies have revealed an extraordinary diversity of protein complexes involved in the biogenesis of cilia during each cell cycle. Mutations in components of these complexes are at the heart of human ciliopathies such as Nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), Bardet-Biedl syndrome (BBS) and Joubert syndrome (JBTS). Despite intense studies, proteins in some of these complexes, such as the NPHP1-4-8 and the MKS, remain poorly understood. Using a combination of computational analyses Dr.Aravind and this team studied these complexes to identify novel domains in them which might throw new light on their functions and evolutionary origins. They identified both catalytically active and inactive versions of transglutaminase-like (TGL) peptidase domains in key ciliary/centrosomal proteins CC2D2A/MKS6, CC2D2B, CEP76 and CCDC135. These ciliary TGL domains appear to have originated from prokaryotic TGL domains that act as peptidases, either in a prokaryotic protein degradation system with the MoxR AAA+ ATPase, the precursor of eukaryotic dyneins and midasins, or in a peptide-ligase system with an ATP-grasp enzyme comparable to tubulin-modifying TTL proteins. They suggest that active ciliary TGL proteins are part of a cilia-specific peptidase system that might remove tubulin modifications or cleave cilia- localized proteins, while the inactive versions are likely to bind peptides and mediate key interactions during ciliogenesis. Dr. Aravind and his team observed a vast radiation of C2 domains, which are key membrane-localization modules, in multiple ciliary proteins, including those from the NPHP1-4-8 and the MKS complexes, such as CC2D2A/MKS6, RPGRIP1, RPGRIP1L, NPHP1, NPHP4, C2CD3, AHI1/Jouberin and CEP76, most of which can be traced back to the last common eukaryotic ancestor. Identification of these TGL and C2 domains aid in the proper reconstruction of the Y-shaped linkers, which are key structures in the transitional zone of cilia, by allowing precise prediction of the multiple membrane-contacting and protein-protein interaction sites in these structures. These findings help decipher key events in the evolutionary separation of the ciliary and nuclear compartments in course of the emergence of the eukaryotic cell. Dr. Aravind's work also contribute to new understanding of transcription factor evolution. Members of the Arabidopsis LSH1 and Oryza G1 (ALOG) family of proteins have been shown to function as key developmental regulators in land plants. However, their precise mode of action remains unclear. Using sensitive sequence and structure analysis, Dr. Aravind and this team showed that the ALOG domains are a distinct version of the N-terminal DNA-binding domain shared by the XerC/D-like, protelomerase, topoisomerase-IA, and Flp tyrosine recombinases. ALOG domains are distinguished by the insertion of an additional zinc ribbon into this DNA-binding domain. In particular, they showed that the ALOG domain is derived from the XerC/D-like recombinases of a novel class of DIRS-1-like retroposons. Copies of this element, which have been recently inactivated, are present in several marine metazoan lineages, whereas the stramenopile Ectocarpus, retains an active copy of the same. Thus, they predict that ALOG domains help establish organ identity and differentiation by binding specific DNA sequences and acting as transcription factors or recruiters of repressive chromatin. They are also found in certain plant defense proteins, where they are predicted to function as DNA sensors. The evolutionary history of the ALOG domain represents a unique instance of a domain, otherwise exclusively found in retroelements, being recruited as a specific transcription factor in the streptophyte lineage of plants. Hence, they add to the growing evidence for derivation of DNA-binding domains of eukaryotic specific TFs from mobile and selfish elements. Dr. Aravind and his team obtained new results that promise to greatly expand our understanding of RNA-dependent restriction systems and the Mediator complex in transcription. The PIWI module, found in the PIWI/AGO superfamily of proteins, is a critical component of several cellular pathways including germline maintenance, chromatin organization, regulation of splicing, RNA interference, and virus suppression. It binds a guide strand which helps it target complementary nucleic strands. They reported the discovery of two divergent, novel families of PIWI modules, the first such to be described since the initial discovery of the PIWI/AGO superfamily over a decade ago. Both families display conservation patterns consistent with the binding of oligonucleotide guide strands. The first family is bacterial in distribution and is typically encoded by a distinctive three-gene operon alongside genes for a restriction endonuclease fold enzyme and a helicase of the DinG family. The second family is found only in eukaryotes. It is the core conserved module of the Med13 protein, a subunit of the CDK8 subcomplex of the transcription regulatory Mediator complex. Based on the presence of the DinG family helicase, which specifically acts on R-loops, they inferred that the first family of PIWI modules is part of a novel RNA-dependent restriction system which could target invasive DNA from phages, plasmids or conjugative transposons. It is predicted to facilitate restriction of actively transcribed invading DNA by utilizing RNA guides. The PIWI family found in the eukaryotic Med13 proteins throws new light on the regulatory switch through which the CDK8 subcomplex modulates transcription at Mediator-bound promoters of highly transcribed genes. They proposed that this involves recognition of small RNAs by the PIWI module in Med13 resulting in a conformational switch that propagates through the Mediator complex

Project Start
Project End
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Budget End
Support Year
7
Fiscal Year
2013
Total Cost
$1,130,047
Indirect Cost
Name
National Library of Medicine
Department
Type
DUNS #
City
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Iyer, Lakshminarayan M; Zhang, Dapeng; Aravind, L (2016) Adenine methylation in eukaryotes: Apprehending the complex evolutionary history and functional potential of an epigenetic modification. Bioessays 38:27-40
Zhang, Dapeng; Burroughs, A Maxwell; Vidal, Newton D et al. (2016) Transposons to toxins: the provenance, architecture and diversification of a widespread class of eukaryotic effectors. Nucleic Acids Res 44:3513-33
Burroughs, A Maxwell; Aravind, L (2016) RNA damage in biological conflicts and the diversity of responding RNA repair systems. Nucleic Acids Res :
Vidal, Newton M; Grazziotin, Ana Laura; Iyer, Lakshminarayan M et al. (2016) Transcription factors, chromatin proteins and the diversification of Hemiptera. Insect Biochem Mol Biol 69:1-13
Meiering, Elizabeth M; Aravind, L (2016) Editorial overview: Sequences and topology: Protein function - synthesizing information from sequence, structure and disorder. Curr Opin Struct Biol 38:vii-ix
Burroughs, A Maxwell; Zhang, Dapeng; Schäffer, Daniel E et al. (2015) Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling. Nucleic Acids Res 43:10633-54
Samanovic, Marie I; Tu, Shengjiang; Novák, Ondřej et al. (2015) Proteasomal control of cytokinin synthesis protects Mycobacterium tuberculosis against nitric oxide. Mol Cell 57:984-94
Dambach, Michael; Sandoval, Melissa; Updegrove, Taylor B et al. (2015) The ubiquitous yybP-ykoY riboswitch is a manganese-responsive regulatory element. Mol Cell 57:1099-109
Mesquita, Rafael D; Vionette-Amaral, Raquel J; Lowenberger, Carl et al. (2015) Genome of Rhodnius prolixus, an insect vector of Chagas disease, reveals unique adaptations to hematophagy and parasite infection. Proc Natl Acad Sci U S A 112:14936-41
Natarajan, Padmaja; Punta, Marco; Kumar, Abhinav et al. (2015) Structure and sequence analyses of Bacteroides proteins BVU_4064 and BF1687 reveal presence of two novel predominantly-beta domains, predicted to be involved in lipid and cell surface interactions. BMC Bioinformatics 16:7

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