Plasmodium falciparum, the human malaria parasite harbors a metastable proteome which is vulnerable to proteotoxic stress conditions encountered during its lifecycle. How parasite’s chaperone machinery is able to maintain its aggregation-prone proteome in functional state, is poorly understood. As HSP70-40 system forms the central hub in cellular proteostasis, we investigated the protein folding capacity of PfHSP70-1 and PfHSP40 chaperone pair and compared it with human orthologs (HSPA1A and DNAJA1). Despite structural similarity, we observed that parasite chaperones and their human orthologs exhibit striking differences in conformational dynamics. Comprehensive biochemical investigations revealed that PfHSP70-1 and PfHSP40 chaperone pair has better protein folding, aggregation inhibition and oligomer remodeling and disaggregase activities than their human orthologs. Chaperone-swapping experiments suggest that PfHSP40 can also efficiently cooperate with human HSP70 to facilitate folding of client-substrate. SPR-derived kinetic parameters reveal that PfHSP40 has higher binding affinity towards unfolded substrate than DNAJA1. Interestingly, the observed slow dissociation rate of PfHSP40-substrate interaction allows PfHSP40 to maintain substrate in folding-competent state to minimize its misfolding. Structural investigation through SAXS gave insights into the conformational architecture of PfHSP70-1 (monomer), PfHSP40 (dimer) and their complex. Overall, our data suggests that parasite has evolved functionally diverged and efficient chaperone machinery which allows human malaria parasite to survive in hostile conditions. The distinct allosteric landscapes and interaction kinetics of plasmodial chaperones open avenues for exploration of small-molecule based antimalarial interventions.

Defective protein folding and accumulation of misfolded proteins is associated with neurodegenerative, cardiovascular, secretory, and metabolic disorders. Efforts are being made to identify small‐molecule modulators or structural‐correctors for conformationally destabilized proteins implicated in various protein aggregation diseases. Using a metastable‐reporter‐based primary screen, we evaluated pharmacological chaperone activity of a diverse class of natural products. We found that a flavonoid glycoside (C‐10, chrysoeriol‐7‐O‐β‐D‐glucopyranoside) stabilizes metastable proteins, prevents its aggregation, and remodels the oligomers into protease‐sensitive species. Data was corroborated with additional secondary screen with disease‐specific pathogenic protein. In vitro and cell‐based experiments showed that C‐10 inhibits α‐synuclein aggregation which is implicated in synucleinopathies‐related neurodegeneration. C‐10 interferes in its structural transition into β‐sheeted fibrils and mitigates α‐synuclein aggregation‐associated cytotoxic effects. Computational modeling suggests that C‐10 binds to unique sites in α‐synuclein which may interfere in its aggregation amplification. These findings open an avenue for comprehensive SAR development for flavonoid glycosides as pharmacological chaperones for metastable and aggregation‐prone proteins implicated in protein conformational diseases.

Background:The emergence of the domestic franchise based leagues has changed the structure of Indian sports and how people view them. Franchises in leagues like the Indian Premier League and Indian Super League have been successful in creating a massive fan following and are able to get them to fill in their stadiums match after match. Fans are one of the most important stakeholders when it comes to franchises/clubs/teams as they are an essential source of revenue for every club or team. The main purpose of this research was to try and understand the factors that influence an individual to identify themselves as a fan of a certain team in the Indian sports sector i.e. Indian Premier League.Methods: A total of 86 subjects were selected using a purposive sampling technique. A questionnaire consisting of questions pertaining to fan loyalty was used for the data collection. The research conducted was only restricted to the IPL as it is the only league that has been in existence for more than 5 years.Results:It was observed that 26.2% of the respondents supported Mumbai Indians (MI) and 26.1 % supported Chennai Super Kings (CSK). On the other hand, least support was for Kings XI Punjab (KXIP) i.e 2.9% only.The results also indicated that 76.8% fans have been following teams since the inception of the franchise which would interest franchises in other leagues as capturing them early could lead to retention and less cost spent on acquiring new fans later on.Conclusion: Factors influencing fan loyalty such as celebrity involvement, team performance, in-stadia experience and Star players were identified. The fan sector in Indian Sports is in its nascent stages presently and it will help the franchises in generating a significant amount of revenue if they can convert individuals into fans.