Patrick D'Silva

Patrick D'Silva
Indian Institute of Science | IISC · Department of Biochemistry

Ph.D (Biochemsitry)

About

72
Publications
9,564
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2,392
Citations
Additional affiliations
January 2007 - present
Indian Institute of Science
Position
  • Research Associate

Publications

Publications (72)
Preprint
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Reactive carbonyl species (RCS) such as methylglyoxal and glyoxal are potent glycolytic intermediates that extensively damage cellular biomolecules leading to genetic aberration and protein misfolding. Hence, RCS levels are crucial indicators in the progression of various pathological diseases. Besides the glyoxalase system, emerging studies report...
Article
Plants being sessile are prone to genotoxin‐induced macromolecule damage. Among the inevitable damaging agents are reactive carbonyls that induce glycation of DNA, RNA and proteins to result in the build‐up of advanced glycated end products. However, it is unclear how plants repair glycated macromolecules. DJ‐1/PARK7 members are a highly conserved...
Article
Mitochondria are indispensable eukaryotic organelle required for diverse cellular functions. Mitochondrial health depends on the biogenesis of diverse mitochondrial proteins mediated by specialized protein transport machinery from outer and inner membranes called translocases. The carrier translocase (also known as TIM22 complex) is a unique evolut...
Article
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Congenital Sideroblastic Anemias (CSA) is a group of rare genetic disorders characterized by the abnormal accumulation of iron in erythrocyte precursors. A common hallmark underlying these pathological conditions is mitochondrial dysfunction due to altered protein homeostasis, heme biosynthesis, and oxidative phosphorylation. A clinical study on co...
Article
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Mitochondrial protein translocation is an intricately regulated process that requires dedicated translocases at the outer and inner membranes. The presequence translocase complex, TIM23, facilitates most of the import of preproteins containing presequences into the mitochondria, and its primary structural organization is highly conserved. As part o...
Article
Dynamic changes in mitochondrial shape and size are vital for mitochondrial health and for tissue development and function. Adult Drosophila indirect flight muscles contain densely packed mitochondria. We show here that mitochondrial fusion is critical during early muscle development (in pupa) and that silencing of the outer mitochondrial membrane...
Article
Mitochondrial biogenesis requires efficient sorting of various proteins into different mitochondrial sub-compartments mediated by dedicated protein machinery present in the outer and inner membrane. Among them, the TIM22 complex enables the integration of complex membrane proteins with internal targeting signals into the inner membrane. Although th...
Article
Full-text available
Mgr2, a newly identified subunit of the TIM23 complex function as a gatekeeper of presequence translocase, thereby maintains quality control of inner membrane preproteins sorting. However, precise recruitment of the Mgr2 subunit to the core channel and how it influences the assembly of the TIM23 complex during lateral sorting of preproteins are poo...
Article
Full-text available
Mitochondria are indispensable organelles that perform critical cellular functions, including energy metabolism, neurotransmission, and synaptic maintenance. Mitochondrial dysfunction and impairment in the organellar homeostasis are key hallmarks implicated in the progression of neurodegenerative disorders. The members of DJ-1/ThiJ/PfpI family are...
Article
The role of mitochondria within a cell has grown beyond being the prime source of cellular energy to one of the major signaling platforms. Recent evidence provides several insights into the crucial roles of mitochondrial chaperones in regulating the organellar response to external triggers. The mitochondrial Hsp70 (mtHsp70/Mortalin/Grp75) chaperone...
Article
Full-text available
Biocompatible nanoparticles having intrinsic ability to mimic the cellular antioxidant enzymes are potential candidates for the development of new therapeutics for various oxidative stress related disorders. However, the understanding of interaction and mechanistic crosstalk between the nanoparticles and the cellular biomolecules is limited. Here w...
Article
Nanomaterials with enzyme-like activities (nanozymes) attracts significant interest due to their therapeutic potential for the treatment of various diseases. Herein, we report that a Mn3O4 nanozyme functionally mimic three major antioxidant enzymes, i.e. superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and the multienzyme...
Article
Nanomaterials with enzyme-like activities (nanozymes) attracts significant interest due to their therapeutic potential for the treatment of various diseases. Herein, we report that a Mn3O4 nanozyme functionally mimic three major antioxidant enzymes, i.e. superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) and the multienzyme...
Article
Full-text available
Mitochondria are organelles indispensable for maintenance of cellular energy homeostasis. Most mitochondrial proteins are nuclear encoded and are imported into the matrix compartment where they are properly folded. This process is facilitated by the mitochondrial heat shock protein 70 (mtHsp70), a chaperone contributing to mitochondrial protein qua...
Chapter
Iron-sulfur (Fe-S) clusters serve as a fundamental inorganic constituent of living cells ranging from bacteria to human. The importance of Fe-S clusters is underscored by their requirement as a co-factor for the functioning of different enzymes and proteins. The biogenesis of Fe-S cluster is a highly coordinated process which requires specialized c...
Article
Full-text available
Methylglyoxal (MG) is a key signaling molecule resulting from glycolysis and other metabolic pathways. During abiotic stress, MG levels accumulate to toxic levels in affected cells. However, MG is routinely detoxified through the action of DJ1/PARK7/Hsp31 proteins that are highly conserved across kingdoms and mutations in such genes are associated...
Article
Full-text available
Mitochondrial life-cycle and protein import are intricate cellular processes, which require precise coordination between transport machineries of outer and inner mitochondrial membranes. Presequence translocase performs indispensable function of translocating preproteins having N-terminal targeting sequences across the inner membrane. Tim23 forms t...
Article
Full-text available
Mitochondrial J-proteins play a critical role in governing Hsp70 activity and hence, are essential for organellar protein translocation and folding. In contrast to yeast which has a single J-protein Pam18, humans involve two J-proteins DnaJC15 and DnaJC19, associated with contrasting cellular phenotype, to transport proteins into the mitochondria....
Article
Full-text available
Methylglyoxal (MG) is a reactive metabolic intermediate generated during various cellular biochemical reactions, including glycolysis. Accumulation of MG indiscriminately modifies proteins, including important cellular antioxidant machinery, and leading to severe oxidative stress, which is implicated in multiple neurodegenerative disorders, aging a...
Article
Full-text available
Biogenesis of iron-sulfur (Fe-S) cluster is an indispensable process in living cells. In mammalian mitochondria, the initial step of Fe-S cluster assembly process is assisted by NFS1-ISD11 complex, which delivers sulfur to the scaffold protein ISCU during Fe-S cluster synthesis. Although, ISD11 is an essential protein but its cellular role in the F...
Article
A new carbazole based tetraimidazole ligand 1,3,6,8-tetra(1H-imidazol-1-yl)-9-methyl-9H-carbazole (L) has been synthesized. The unsymmetrical nature of L as well as the rotational freedom of imidazole donor moieties around C-N bond make it a special building unit, which upon treat-ment with cis-(tmeda)Pd((NO3)2 produced an unprecedent-ed single lin...
Article
Novel isoselenazoles with high glutathione peroxidase (GPx) and peroxiredoxin (Prx) activities provide remarkable cytoprotection to human cells, mainly by exhibiting antioxidant activities in the presence of cellular thiols. The cytotoxicity of the isoselenazoles is found to be significantly lower than that of ebselen, which is being clinically eva...
Article
Full-text available
Nanomaterials with enzyme-like properties has attracted significant interest, although limited information is available on their biological activities in cells. Here we show that V2O5 nanowires (Vn) functionally mimic the antioxidant enzyme glutathione peroxidase by using cellular glutathione. Although bulk V2O5 is known to be toxic to the cells, t...
Article
Full-text available
Redox imbalance generates multiple cellular damages leading to oxidative stress-mediated pathological conditions such as neurodegenerative diseases and cancer progression. Therefore, maintenance of reactive oxygen species (ROS) homeostasis is most important that involves well-defined antioxidant machinery. In the present study, we have identified f...
Article
Full-text available
Mitochondrial Hsp70 (mtHsp70) is essential for a vast repertoire of functions including protein import, requiring effective interdomain communication for efficient partner-protein interactions. However, in vivo functional significance of allosteric regulation in eukaryotes is poorly defined. Utilizing integrated biochemical and yeast genetic approa...
Article
Full-text available
Mitochondria are indispensable organelles implicated in multiple aspects of cellular processes, including tumorigenesis. Heat-Shock Proteins play a critical regulatory role in accurately delivering the nuclear encoded proteins through membrane-bound presequence translocase (Tim23-complex) machinery. Although, altered expression of mammalian presequ...
Article
Full-text available
Mitochondria have a central role in the intrinsic pathway of apoptosis and involve activation of several transmembrane channels leading to release of death factors. Reduced expression of a mitochondrial J-protein DnaJC15 was associated with the development of chemoresistance in ovarian cancer cells. DnaJC15 was found to be a part of mitochondrial p...
Article
Full-text available
Iron-sulfur (Fe-S) clusters are versatile cofactors involved in regulating multiple physiological activities, including energy generation through cellular respiration. Initially, the Fe-S clusters are assembled on a conserved scaffold protein ISCU in coordination with iron and sulfur donor proteins in human mitochondria. Loss of ISCU function leads...
Article
Full-text available
Tim23 is an essential channel-forming subunit of the presequence translocase recruiting multiple components for assembly of the core complex, thereby regulating the protein translocation process. However, understanding of the precise interaction of subunits associating with Tim23 remains largely elusive. Our findings highlight that transmembrane he...
Article
Kinetics and thermodynamics of amide hydrogen exchange in proteins can be investigated with two-dimensional (13) CO-(15) N NMR correlation experiments. The spectra are acquired with high resolution and sensitivity. A single type of experiment on one sample serves to characterize hydrogen-deuterium fractionation factors and hydrogen-exchange rates t...
Article
Full-text available
Heat shock protein information resource (HSPIR) is a concerted database of six major heat shock proteins (HSPs), namely, Hsp70, Hsp40, Hsp60, Hsp90, Hsp100 and small HSP. The HSPs are essential for the survival of all living organisms, as they protect the conformations of proteins on exposure to various stress conditions. They are a highly conserve...
Article
Full-text available
Parkinson's disease (PD) is the second most prevalent progressive neurological disorder commonly associated with impaired mitochondrial function in dopaminergic neurons. Although familial PD is multifactorial in nature, a recent genetic screen involving PD patients identified two mitochondrial Hsp70 variants (P509S and R126W) that are suggested in...
Article
Full-text available
J-proteins are obligate cochaperones of Hsp70s and stimulate their ATPase activity via the J-domain. Although the functions of J-proteins have been well understood in the context of Hsp70s, their additional co-evolved "physiological functions" are still elusive. We report here the solution structure and mechanism of novel iron-mediated functional r...
Article
Full-text available
The evolutionary diversity of the HSP70 gene family at the genetic level has generated complex structural variations leading to altered functional specificity and mode of regulation in different cellular compartments. By utilizing Saccharomyces cerevisiae as a model system for better understanding the global functional cooperativity between Hsp70 p...
Presentation
The evolutionary diversity of HSP70-gene family at the genetic level has generated complex structural variations leading to altered functional specificity and mode of regulation in different cellular compartments. By utilizing Saccharomyces cerevisiae as a model system for better understanding the global functional cooperativity between Hsp70 paral...
Article
Full-text available
Sequence specific resonance assignment constitutes an important step towards high-resolution structure determination of proteins by NMR and is aided by selective identification and assignment of amino acid types. The traditional approach to selective labeling yields only the chemical shifts of the particular amino acid being selected and does not h...
Article
Three-dimensional (3D) structure determination of proteins is benefitted by long-range distance constraints comprising the methyl groups, which constitute the hydrophobic core of proteins. However, in methyl groups (of Ala, Ile, Leu, Met, Thr and Val) there is a significant overlap of ¹³C and ¹H chemical shifts. Such overlap can be resolved using t...
Article
Full-text available
Magmas, a conserved mammalian protein essential for eukaryotic development, is overexpressed in prostate carcinomas and cells exposed to granulocyte-macrophage colony-stimulating factor (GM-CSF). Reduced Magmas expression resulted in decreased proliferative rates in cultured cells. However, the cellular function of Magmas is still elusive. In this...
Article
Full-text available
Mitochondria biogenesis requires the import of several precursor proteins that are synthesized in the cytosol. The mitochondrial heat shock protein 70 (mtHsp70) machinery components are highly conserved among eukaryotes, including humans. However, the functional properties of human mtHsp70 machinery components have not been characterized among all...
Data
Data collection of type III and type IV A. thaliana J-proteins .
Data
Structural classification of A. thaliana type III and type IV J-proteins. In total, 92 type III J-proteins and four type IV J-like proteins have been identified in A. thaliana genome. The highly diverged A. thaliana type III J-proteins contain additional zinc-finger domains along with J-domain such as C2H2, A2L, DPH, PhnA, PHD, ZF-HYPF, PRIM ZN, an...
Article
Plants are sessile organisms that have evolved a variety of mechanisms to maintain their cellular homeostasis under stressful environmental conditions. Survival of plants under abiotic stress conditions requires specialized group of heat shock protein machinery, belonging to Hsp70:J-protein family. These heat shock proteins are most ubiquitous type...
Article
Full-text available
Import of proteins across the inner mitochondrial membrane through the Tim23:Tim17 translocase requires the function of an essential import motor having mitochondrial 70-kDa heat-shock protein (mtHsp70) at its core. The heterodimer composed of Pam18, the J-protein partner of mtHsp70, and the related protein Pam16 is a critical component of this mot...
Article
Biogenesis of Fe-S clusters is an essential process [1]. In both Escherichia coli and Saccharomyces cerevisiae, insertion of clusters into an apoprotein requires interaction between a scaffold protein on which clusters are assembled and a molecular chaperone system--an unusually specialized mitochondrial Hsp70 (mtHsp70) and its J protein cochaperon...
Article
Hsp70s are arguably the most ubiquitous and versatile molecular chaperones, promoting folding, transport across membranes, and proteolysis of client proteins. The biochemical basis of these talents is the ability of Hsp70 to reversibly interact with client protein in a manner precisely regulated by cycles of binding, hydrolysis, and release of aden...
Article
Full-text available
Translocation of proteins across the mitochondrial inner membrane is an essential process requiring an import motor having mitochondrial Hsp70 (mtHsp70) at its core. The J protein partner of mtHsp70, Pam18, is an integral part of this motor, serving to stimulate the ATPase activity of mtHsp70. Pam16, an essential protein having an inactive J domain...
Article
Full-text available
Ssq1, a specialized yeast mitochondrial Hsp70, plays a critical role in the biogenesis of proteins containing Fe-S clusters through its interaction with Isu, the scaffold on which clusters are built. Two substitutions within the Ssq1 substrate binding cleft, both of which severely reduced affinity for Isu, had very different effects in vivo. Cells...
Article
Full-text available
Preproteins synthesized on cytosolic ribosomes, but destined for the mitochondrial matrix, pass through the presequence translocase of the inner membrane. Translocation is driven by the import motor, having at its core the essential chaperone mtHsp70 (Ssc1 in yeast). MtHsp70 is tethered to the translocon channel at the matrix side of the inner memb...
Article
Full-text available
The major Hsp70 of the mitochondrial matrix (Ssc1 in yeast) is critically important for the translocation of proteins from the cytosol, across the mitochondrial inner membrane, and into the matrix. Tim44, a peripheral inner membrane protein with limited sequence similarity to the J domain of J-type cochaperones, tethers Ssc1 to the import channel....
Article
Hsp70 of the mitochondrial matrix (mtHsp70) provides a critical driving force for the import of proteins into mitochondria. Tim44, a peripheral inner-membrane protein, tethers it to the import channel. Here, regulated interactions were found to maximize occupancy of the active, adenosine 5'-triphosphate (ATP)-bound mtHsp70 at the channel through it...
Article
Polarity-sensitive fluorescent probes like 8-anilino-1-naphthalenesulphonate (ANS) and 1,1′-bis(4-anilino-5-naphthalenesulphonic acid (bis-ANS) have been frequently used to detect equilibrium folding intermediates like the molten globule state, as the formation of the latter involves increase in hydrophobic exposure. The ability of these fluorescen...