| 51 |
IPD2655 |
Aggregation of respiratory complex subunits marks the onset of proteotoxicity in proteasome inhibited cells |
Dr Swasti Raychaudhuri |
Proteostasis is maintained by optimum expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. Here, using quantitative proteomics and microscopy we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein-destabilization event during short-term...
Proteostasis is maintained by optimum expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers protein aggregation and is implicated in many age-related pathologies. Here, using quantitative proteomics and microscopy we show that aggregation of many nuclear-encoded mitochondrial proteins is an early protein-destabilization event during short-term proteasome inhibition. Among these, Respiratory Chain Complex (RCC) subunits represent a group of functionally related proteins consistently forming aggregates under multiple proteostasis-stresses with varying aggregation-propensities. Sequence analysis reveals that several RCC subunits, irrespective of cleavable mitochondrial targeting sequence (MTS), contain low complexity regions (LCR) at N-terminus. Using different chimeric and mutant constructs we show that these low complexity regions partially contribute to intrinsic instability of multiple RCC subunits. Taken together, we propose that physicochemically driven aggregation of unassembled RCC subunits destabilizes their functional assembly inside mitochondria. This deregulates the biogenesis of respiratory complexes and marks the onset of mitochondrial dysfunction.
Read more
...Read less
|
Centre for Cellular & Molecular Biology (CCMB |
Shotgun proteomics, Gel-based experiment |
2024-11-16 |
30682348
|
| 52 |
IPD3807 |
QUATERNARY AND QUINARY ORGANIZATION OF RESPIRATORY COMPLEX SUBUNITS TO ADAPT PROTEOSTASIS-STRESS |
Dr. Swasti Raychaudhuri |
Phase separation and reversible aggregation of proteins is a well-recognized adaptive strategy to survive stress. Here, we show that RCC subunits are engaged into improved super-quaternary organizations inside mitochondria during proteostasis stress. Assembly and oligomeric organizations of Complex II and V are consolidated while Complex I, III and IV are...
Phase separation and reversible aggregation of proteins is a well-recognized adaptive strategy to survive stress. Here, we show that RCC subunits are engaged into improved super-quaternary organizations inside mitochondria during proteostasis stress. Assembly and oligomeric organizations of Complex II and V are consolidated while Complex I, III and IV are increasingly incorporated into respiratory supercomplexes in multiple cell-lines with different proteostasis and metabolic demands. Further, our results suggest that improved supra-organization of respiratory complexes (iSRC) is an outcome of conformational optimization towards better enzyme activity and co-terminus to appearance of aggregates of RCC subunits in stressed cells. Simultaneous reversion of iSRC and disappearance of aggregates during stress-withdrawal indicates complementarity between these quaternary and quinary proteome-reorganization mechanisms. iSRC appears to be the pre-emptive and deterministic ensemble over stochastic aggregation as it offers direct fitness-benefit.
Read more
...Read less
|
Centre for Cellular & Molecular Biology (CCMB |
Shotgun proteomics |
2024-11-16 |
|
| 53 |
IPD1344 |
QUATERNARY AND QUINARY ORGANIZATION OF RESPIRATORY COMPLEX SUBUNITS TO ADAPT PROTEOSTASIS-STRESS |
Dr Swasti Raychaudhuri |
Phase separation and reversible aggregation of proteins is a well-recognized adaptive strategy to survive stress. Here, we show that RCC subunits are engaged into improved super-quaternary organizations inside mitochondria during proteostasis stress. Assembly and oligomeric organizations of Complex II and V are consolidated while Complex I, III and IV are...
Phase separation and reversible aggregation of proteins is a well-recognized adaptive strategy to survive stress. Here, we show that RCC subunits are engaged into improved super-quaternary organizations inside mitochondria during proteostasis stress. Assembly and oligomeric organizations of Complex II and V are consolidated while Complex I, III and IV are increasingly incorporated into respiratory supercomplexes in multiple cell-lines with different proteostasis and metabolic demands. Further, our results suggest that improved supra-organization of respiratory complexes (iSRC) is an outcome of conformational optimization towards better enzyme activity and co-terminus to appearance of aggregates of RCC subunits in stressed cells. Simultaneous reversion of iSRC and disappearance of the aggregates during stress-withdrawal indicates complementarity between these quaternary and quinary proteome-reorganization mechanisms. iSRC appears to be the pre-emptive and deterministic ensemble over stochastic aggregation as it offers direct fitness-benefit.
Read more
...Read less
|
Centre for Cellular & Molecular Biology (CCMB |
Shotgun proteomics |
2024-11-16 |
32878939
|
| 54 |
IPD6047 |
Nuclear-injuries by aberrant dynein-forces defeat proteostatic purposes of Lewy Body-like InclusionsNuclear-injuries by aberrant dynein-forces defeat proteostatic purposes of Lewy Body-like Inclusions |
Dr Swasti Raychaudhuri |
Biogenesis of inclusion bodies (IBs) facilitates protein quality control (PQC). Canonical aggresomes execute degradation of misfolded proteins while non-degradable amyloids quarantine into Insoluble Protein Deposits. Lewy Bodies (LBs) are well-known neurodegenerative IBs of α-Synuclein but PQC-benefits and drawbacks associated with LBs remain underexplored. Here, we report that a crosstalk between...
Biogenesis of inclusion bodies (IBs) facilitates protein quality control (PQC). Canonical aggresomes execute degradation of misfolded proteins while non-degradable amyloids quarantine into Insoluble Protein Deposits. Lewy Bodies (LBs) are well-known neurodegenerative IBs of α-Synuclein but PQC-benefits and drawbacks associated with LBs remain underexplored. Here, we report that a crosstalk between LBs and aggresome-like IBs of α-Synuclein (Syn-aggresomes) buffer amyloidogenic α-Synuclein load. LBs possess unorthodox PQC-capacities of self-quarantining Syn-amyloids and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of LBs by facilitating spontaneous degradation of soluble α-Synuclein and opportunistic turnover of Syn-amyloids. LBs overgrow at the perinucleus once amyloidogenesis sets in and are misidentified by cytosolic BICD2 as cargos for motor-protein dynein. Simultaneously, microtubules surrounding the perinuclear LBs are distorted misbalancing the dynein motor-force on nucleoskeleton leading to widespread lamina injuries. Like typical Laminopathies, nucleocytoplasmic mixing, DNA-damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of LBs.
Read more
...Read less
|
Centre for Cellular & Molecular Biology (CCMB |
Gel-based experiment |
2024-11-16 |
38477372
|
| 55 |
IPD6128 |
Stings on wings: venom proteomics and tissue transcriptomics of the lesser banded hornet, Vespa affinis |
Dr Kartik Sunagar |
The project aims at unraveling the venom repertoire of the lesser banded hornet (Vespa affinis) and investigate the regimes of natural selection underpinning their venom evolution. The study also sheds light on the clinical repercussions of the V. affinis venom.
|
Evolutionary Venomics Lab, Center for Ecological Sciences, Indian Institute of Science, Bangalore, India |
Shotgun proteomics |
2024-11-24 |
36601583
|
| 56 |
IPD8910 |
A wolf in another wolf’s clothing: Post-genomic regulation dictates venom profiles of medically-important cryptic kraits in India |
Dr. Kartik Sunagar |
This study investigates the widespread cryptic Bungarus caeruleus (Comman krait) in India and clinical repercussions of their bits by implementing multidisciplinary approach involving proteomics, transcripomics, and assessment of toxicity and efficacy of currently marketed anivenoms. The study also aims at understanding the evolutionary relationships between these phenotypically simillar kraits.
|
Evolutionary Venomics Lab, Center for Ecological Sciences, Indian Institute of Science, Bangalore, India |
Shotgun proteomics |
2024-11-24 |
33477742
|
| 57 |
IPD3987 |
The preclinical evaluation of a second-generation antivenom for treating snake envenoming in India |
Dr. Kartik Sunagar |
In this study, by employing chromatographic purification of the bulk, we have significantly enhanced the preclinical performance of the conventional Indian antivenom product. The effectiveness of the test batches of this ‘second-generation’ antivenom was evaluated using a variety of in vitro and in vivo preclinical assays, including venom recognition and...
In this study, by employing chromatographic purification of the bulk, we have significantly enhanced the preclinical performance of the conventional Indian antivenom product. The effectiveness of the test batches of this ‘second-generation’ antivenom was evaluated using a variety of in vitro and in vivo preclinical assays, including venom recognition and toxicity and pathology neutralisation. The outcomes of these experiments demonstrated the significantly superior performance of the purified product over all other major commercial Indian antivenoms.
Read more
...Read less
|
Evolutionary Venomics Lab, Center for Ecological Sciences, Indian Institute of Science, Bangalore, India |
Shotgun proteomics |
2024-11-24 |
35324665
|
| 58 |
IPD1168 |
To the islands their own: Venomics of the enigmatic Andaman cobra (N. sagittifera) and the preclinical failure of Indian antivenoms in Andaman and Nicobar Islands |
Dr. Kartik Sunagar |
In this study, we unveil the venom composition, biochemistry, pharmacological activity, and potency of the Andaman cobra (N. sagittifera).
|
Evolutionary Venomics Lab, Center for Ecological Sciences, Indian Institute of Science, Bangalore, India |
Shotgun proteomics |
2024-11-24 |
34759827
|
| 59 |
IPD7258 |
The Arabian cousin: Comparative venomics of Daboia palaestinae and Daboia russelii |
Dr. Kartik Sunagar |
In this study, to unravel the influence of phylogenetic divergence and biogeography in shaping the composition and activity of Daboia venoms, we comparatively investigated the venoms of D. russelii from western India and D. palaestinae from Israel.
|
Evolutionary Venomics Lab, Center for Ecological Sciences, Indian Institute of Science, Bangalore, India |
Shotgun proteomics |
2024-11-24 |
36355975
|
| 60 |
IPD3822 |
Fangs in the ghats: preclinical insights into the medical importance of endemic pit vipers from the Western Ghats |
Dr. Kartik Sunagar |
The socioeconomic burden of snakebite in India is largely attributed to the ‘big four’ snakes, completely neglecting the considerable impact of envenoming by many other snake species. Bites from the so-called ‘neglected many’ are often treated with a polyvalent antivenom that is manufactured against the ‘big four’ snakes - a...
The socioeconomic burden of snakebite in India is largely attributed to the ‘big four’ snakes, completely neglecting the considerable impact of envenoming by many other snake species. Bites from the so-called ‘neglected many’ are often treated with a polyvalent antivenom that is manufactured against the ‘big four’ snakes - a strategy that has been widely documented to fail. Yet, specific antivenoms are not commercially manufactured against these snakes. While the medical importance of various species of cobras, saw-scaled vipers, and kraits is very well-known, the clinical impact of pit vipers from the rainforests of the Western Ghats, northeastern India, and Andaman and Nicobar islands has remained elusive. Amongst the 90+ species of snakes found in the Western Ghats, the hump-nosed (Hypnale hypnale), Malabar (Craspedocephalus malabaricus) and bamboo (Craspedocephalus gramineus) pit vipers can potentially inflict clinically severe envenoming in humans. To evaluate the severity of toxicity inflicted by these snakes, we characterised their venom composition, biochemical and pharmacological activities, and toxicity- and morbidity-inducing potentials. Our findings highlight the therapeutic inadequacies of the generic Indian and Hypnale-specific Sri Lankan polyvalent antivenoms in neutralising morbidity and mortality resulting from pit viper envenomings and underscore the need for a regional antivenom therapy in India.
Read more
...Read less
|
Evolutionary Venomics Lab, Center for Ecological Sciences, Indian Institute of Science, Bangalore, India |
Shotgun proteomics |
2024-11-24 |
37298463
|
