Showing papers by "Sudip Kundu published in 2021"
TL;DR: In this article, the authors identify the potential mechanisms of host cell subversion by building a K. pneumoniae-human interactome based on rigorous computational methodology and find that the putative host targets inferred from the predicted interactome were found to be functionally enriched in the host's immune surveillance system and allied functions like apoptosis, hypoxia, etc.
Abstract: Klebsiella pneumoniae is a leading cause of pneumonia and septicemia across the world. The rapid emergence of multidrug-resistant K. pneumoniae strains necessitates the discovery of effective drugs against this notorious pathogen. However, there is a dearth of knowledge on the mechanisms by which this deadly pathogen subverts host cellular machinery. To fill this knowledge gap, our study attempts to identify the potential mechanisms of host cell subversion by building a K. pneumoniae-human interactome based on rigorous computational methodology. The putative host targets inferred from the predicted interactome were found to be functionally enriched in the host's immune surveillance system and allied functions like apoptosis, hypoxia, etc. A multifunctionality-based scoring system revealed P53 as the most multifunctional protein among host targets accompanied by HIF1A and STAT1. Moreover, mining of host protein-protein interaction (PPI) network revealed that host targets interact among themselves to form a network (TTPPI), where P53 and CDC5L occupy a central position. The TTPPI is composed of several inter complex interactions which indicate that K. pneumoniae might disrupt functional coordination between these protein complexes through targeting of P53 and CDC5L. Furthermore, we identified four pivotal K. pneumoniae-targeted transcription factors (TTFs) that are part of TTPPI and are involved in generating host's transcriptional response to K. pneumoniae-mediated sepsis. In a nutshell, our study identifies some of the pivotal molecular targets of K. pneumoniae which primarily correlate to the physiological response of host during K. pneumoniae-mediated sepsis.
3 citations
TL;DR: Side‐by‐side comparison of molecular principles underlying controlled protein and mRNA degradation in yeast unravels their remarkable mechanistic similarities and suggests how the intrinsic structural features of the two molecular species, at two different levels of the central dogma, regulate their half‐lives on genome scale.
Abstract: Precise control of protein and messenger RNA (mRNA) degradation is essential for cellular metabolism and homeostasis. Controlled and specific degradation of both molecular species necessitates their engagements with the respective degradation machineries; this engagement involves a disordered/unstructured segment of the substrate traversing the degradation tunnel of the machinery and accessing the catalytic sites. However, while molecular factors influencing protein degradation have been extensively explored on a genome scale, and in multiple organisms, such a comprehensive understanding remains missing for mRNAs. Here, we analyzed multiple genome-scale experimental yeast mRNA half-life data in light of experimentally derived mRNA secondary structures and protein binding data, along with high-resolution X-ray crystallographic structures of the RNase machines. Results unraveled a consistent genome-scale trend that mRNAs comprising longer terminal and/or internal unstructured segments have significantly shorter half-lives; the lengths of the 5'-terminal, 3'-terminal, and internal unstructured segments that affect mRNA half-life are compatible with molecular structures of the 5' exo-, 3' exo-, and endoribonuclease machineries. Sequestration into ribonucleoprotein complexes elongates mRNA half-life, presumably by burying ribonuclease engagement sites under oligomeric interfaces. After gene duplication, differences in terminal unstructured lengths, proportions of internal unstructured segments, and oligomerization modes result in significantly altered half-lives of paralogous mRNAs. Side-by-side comparison of molecular principles underlying controlled protein and mRNA degradation in yeast unravels their remarkable mechanistic similarities and suggests how the intrinsic structural features of the two molecular species, at two different levels of the central dogma, regulate their half-lives on genome scale.
3 citations
TL;DR: In this article, the role of buried and partially exposed charge reversal mutations (CRM) in enhancing thermal stability was investigated on 1550 M-T/HT orthologous protein pairs with remarkable structural and topological similarity, and it was shown that proper designing of few partially exposed and buried CRMs significantly contributes to thermal stability by altering the short distance electrostatic interactions.
Abstract: Do charge reversal mutations (CRM) naturally occur in mesophilic-thermophilic/hyperthermophilic (M-T/HT) orthologous proteins? Do they contribute to thermal stability by altering charge-charge interactions? A careful investigation on 1550 M-T/HT orthologous protein pairs with remarkable structural and topological similarity extracts the role of buried and partially exposed CRMs in enhancing thermal stability. Our findings could assist in engineering thermo-stable variants of proteins. SIGNIFICANCEProtein engineering is one of the hot topics for decades specifically for its applications in different fields like de-novo protein design, directed evolution, making highly stable variants for food and drug industry etc. Proteins from organisms living in extreme environments are therefore a matter of common interest for scientists from different disciplines. Over three decades of study has already found several sequence and structural adaptations related to thermal stability, while charge reversal study remains ignored to a large extent. Influenced by natures strategy, our study provides a systemic understanding of how proper designing of few partially exposed and buried CRMs significantly contributes to thermal stability by altering the short distance electrostatic interactions.