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Nirupa Nagaratnam Eric Hamilton Karunanayake Kamani Hemamala Tennekoon Sameera Ranganath Samarakoon Karthika Mayan 《Bioinformation》2014,10(8):512-517
Human lymphatic filariasis (HLF) is a neglected tropical disease which threatens nearly 1.4 billion people in 73 countries
worldwide. Wuchereria bancrofti is the major causative agent of HLF and it closely resembles cattle filarial parasite Setaria digitata.
Due to difficulties in procuring W. bancrofti parasite material, S. digitata cDNA library has been constructed to identify novel drug
targets against HLF and many of the cDNA sequences are yet to be assigned structure and function. In this study, a 549 bp long
cDNA (sdrbp) has been sequenced and characterized in silico. The shortest ORF of 249 bp from the isolated cDNA encodes a
polypeptide of 82 amino acids and shows an amino acid identity of 54% with the RRM domain of human cleavage stimulation
factor-64 kDa subunit (CstF-64). Structure of the protein (sdRBP) obtained by homology modelling using RRM of CstF-64 as
template adopts classical RRM topology (β1α1β2β3α2β4). sdRBP model built was validated by superimposition tools and
Ramachandran plot analysis. CstF-64 plays an important role in pre-mRNA polyadenylation by interacting with specific GU-rich
downstream sequence element. Molecular docking studies of sdRBP with different RNA molecules revealed that sdRBP has greater
binding affinity to GU-rich RNA and comparable results were obtained upon similar docking of RRM of CstF-64 with the same
RNA molecules. Therefore, sdRBP is likely to perform homologous function in S. digitata. This study brings new dimensions to the
functional analysis of RNA binding proteins of S. digitata and their evaluation as new drug targets against HLF. 相似文献
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A. Umano K. Fang Z. Qu J.B. Scaglione S. Altinok C.J. Treadway E.T. Wick E. Paulakonis C. Karunanayake S. Chou T.M. Bardakjian P. Gonzalez-Alegre R.C. Page J.C. Schisler N.G. Brown D. Yan K.M. Scaglione 《The Journal of biological chemistry》2022,298(5)
The spinocerebellar ataxias (SCAs) are a class of incurable diseases characterized by degeneration of the cerebellum that results in movement disorder. Recently, a new heritable form of SCA, spinocerebellar ataxia type 48 (SCA48), was attributed to dominant mutations in STIP1 homology and U box-containing 1 (STUB1); however, little is known about how these mutations cause SCA48. STUB1 encodes for the protein C terminus of Hsc70 interacting protein (CHIP), an E3 ubiquitin ligase. CHIP is known to regulate proteostasis by recruiting chaperones via a N-terminal tetratricopeptide repeat domain and recruiting E2 ubiquitin-conjugating enzymes via a C-terminal U-box domain. These interactions allow CHIP to mediate the ubiquitination of chaperone-bound, misfolded proteins to promote their degradation via the proteasome. Here we have identified a novel, de novo mutation in STUB1 in a patient with SCA48 encoding for an A52G point mutation in the tetratricopeptide repeat domain of CHIP. Utilizing an array of biophysical, biochemical, and cellular assays, we demonstrate that the CHIPA52G point mutant retains E3-ligase activity but has decreased affinity for chaperones. We further show that this mutant decreases cellular fitness in response to certain cellular stressors and induces neurodegeneration in a transgenic Caenorhabditis elegans model of SCA48. Together, our data identify the A52G mutant as a cause of SCA48 and provide molecular insight into how mutations in STUB1 cause SCA48. 相似文献
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Wickramasinghe M. Bandaranayake Sarath P. Gunasekera Subadra Karunanayake 《Phytochemistry》1975,14(9):2043-2048
From the resins of Dipterocarpus hispidus, Dipterocarpus zeylanicus and Doona macrophylla, asiatic (2α,3β,23α-trihydroxyurs-12-en-28-oic) and 2α,3β-dihydroxyurs-12-en-28-oic acids have been isolated. The resin of Doona macrophylla contains ursolic acid and that of Doona congestiflora asiatic acid, 20β-hydroxy-3-oxo dammar-23-ene (Dipterocarpol) and a dihydroxyolean-12-en-28-oic acid. The bark of Dipterocarpus hispidus contains betulinic acid, dipterocarpol, and 3β,20β-dihydroxydammar-23-ene (dammarenediol 20S) whilst the timber contained dipterocarpol and asiatic acid. 相似文献
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Chamithi Karunanayake Richard C Page 《Experimental biology and medicine (Maywood, N.J.)》2021,246(12):1419
The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control. 相似文献
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[(14)C]Streptozotocin was synthesized specifically labelled at three positions in the molecule. The biological activity of synthetic streptozotocin was characterised by studies in vivo of its diabetogenic activity and its dose-response curves. After this characterization the excretion pattern of all three labelled forms of streptozotocin was studied. With [1-(14)C]streptozotocin and [2'-(14)C]streptozotocin the injected radioactivity was excreted (approx. 70% and 80% respectively) mainly in the urine, the greater part of the excretion occurring in the first 6h period; small amounts (approx. 9% and 8% respectively) were found in the faeces. In contrast, with [3'-methyl-(14)C]streptozotocin a much smaller proportion (approx. 42%) of the injected radioactivity was excreted in the urine, the major proportion appearing in the first 6h, whereas approx. 53% of the injected radioactivity was retained in the carcasses. In whole-body radioautographic studies very rapid renal clearance and hepatic accumulation of the injected radioactivity was observed with all three labelled forms of the drug. There was some evidence for biliary and intestinal excretion. Major differences were apparent in the tissue-distribution studies, with each of the three labelled forms, particularly with [3'-methyl-(14)C]streptozotocin. There was no accumulation of [1-(14)C]streptozotocin in the pancreas for the 6h period after administration. However, with [3'-methyl-(14)C]streptozotocin (and also [2'-(14)C]streptozotocin) there was evidence of some pancreatic accumulation after 2h. The results indicate that streptozotocin is subjected to considerable metabolic transformation and to rapid renal clearance. The implication of these suggestions is evaluated with particular reference to the diabetogenic action of streptozotocin. 相似文献
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Ranil Samantha Dassanayake Witharanage Wasana Prasadini Rodrigo Eric Hamilton Karunanayake Ovitigala Vithanage Don Sisira Jagathpriya Weerasena Naduviladath Vishvanath Chandrasekharan 《Bioinformation》2009,3(9):370-374
Expressed sequence tags (ESTs) are an effective approach for discovery of novel genes. In the current study, approximately
250 ESTs of the cattle parasitic nematode Setaria digitata were examined and a cDNA clone identified whose coding
sequence could not be functionally annotated by searching over publicly available genome, protein, EST and STS databases.
Here, we report the extensive characterization of this ORF (UP) and its homologues using a bioinformatic approach.
Uncharacterized protein (SDUP) of S. digitata consists of 204 amino acids with a predicted molecular weight and isoelectric
point of 22.8KDa and 9.94, respectively. A search carried out using SDUP over nucleotide, EST and protein databases at
NCBI, NEMBASE3 and Parasite Genome Database (PGD) identified homologous counterparts from the human parasitic
nematodes Wuchereria bancrofti (WB), Brugia malayi (BM), Onchocerca volvulus (OV), the mouse filarial worm
Litomosoides sigmodontis (LS), swine parasitic nematodes Ascaris suum (AS) and diverged counterparts from the plant
parasitic nematode Meloidogyne hapla (MH) and free living nematodes Caenorhabditis elegans (CE) and Caenorhabditis
briggsae (CB). Phylogenetic analyses revealed the UPs to be undergoing divergent evolution. A search of the ESTs at PGD
showed that UP is expressed in all the stages of BM. Secondary structure analyses of multiply-aligned sequences of
homologues using Jpred server indicated UPs to be rich in beta-pleated structures. TMMHH server and beta barrel finder
programme indicated, UPs to be neither transmembrane or beta barrels proteins but are likely to be globular proteins.
Further, the Motif discovery tool of MEME identified three novel potential motifs for UPS, of which only two are present in
CE, CB & MH. Analyses of UPs using Signal IP, TargetP, Psort servers predicted this group of proteins to be devoid of
signal peptide cleavage sites, are not mitochondrial targeting peptides but appear to be localized to the nucleus, respectively.
Further analyses of the UPs using ScanProsite server for phosphorylation revealed potential sites for cAMP and cGMPdependent
protein kinase, Protein kinase C and Casein kinase II. Putative functional analysis using ProtFun 2.1 Server
indicated UPs to be nonenzymatic, growth factor like protein. Finally, collating all the information derived from
bioinformatic analyses, we conclude that the UPs of nematodes are most likely to be expressed at all stages in the life cycle,
localized to the nucleus, regulated by phosphorylation, rich in betapleated strands and are growth factor like nematode
specific proteins. 相似文献
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Casinader Saverimuttu JK Karunanayake EH Chandrasekharan NV Jayasena SM 《International journal for parasitology》2000,30(2):119-124
Wuchereria bancrofti is the major cause of lymphatic filariasis in humans. Although it is responsible for this immensely morbid and debilitating disease, very little is known of the basic molecular biology of this parasite, and there is a vast lack of knowledge on its gene organisation. In this study, the actin gene of W. bancrofti has been characterised by sequencing a clone isolated from a genomic DNA library of this parasite. The 5' flanking region had a potential TATA box and a putative mRNA initiation site. The gene had five exons encoding 376 amino acids, and four introns ranging in size from 109 to 190bp. The 3' flanking region had a potential polyadenylation signal with the sequence ATTAAA which is a common natural variant of the conventional sequence AATAAA. The gene was AT-rich, with a GC content of 37.2%. Southern blot analysis of W. bancrofti genomic DNA indicated that the gene is possibly found as a single copy. The actin amino acid sequence of W. bancrofti showed a high degree of homology to the actin of many organisms of different taxonomic groups, but the highest homology was observed with the free-living nematode Plectus acuminatus. This suggests that P. acuminatus may bear a close evolutionary relationship to W. bancrofti. 相似文献