Biology subjects

Tewary, S.

Publications and source records attributed to Tewary, S..

3 recordsLinked to original sources

bioRxiv2021

An integrative approach unveils a distal encounter site for rPTPε and phospho-Src complex formation

Protein tyrosine phosphatase: phospho-protein complex structure determination, which requires to understand how specificity is achieved at the protein level remains a significant challenge for protein crystallography and cryoEM due to the transient nature of binding interactions. Using rPTP{varepsilon}D1 and phospho-SrcKD as a model system, we established an integrative workflow involving protein crystallography, SAXS and pTyr-tailored MD simulations to reveal the complex formed between rPTP{varepsilon}D1 and phospho-SrcKD, revealing transient protein-protein interactions distal to the active site. To support our finding, we determined the associate rate between rPTP{varepsilon}D1 and phospho-SrcKD and showed that a single mutation on rPTP{varepsilon}D1 disrupts this transient interaction, resulting in the reduction of association rate and activity. Our simulations suggest that rPTP{varepsilon}D1 employs a binding mechanism involving conformational change prior to the engagement of cSrcKD. This integrative approach is applicable to other PTP: phospho-protein complex determination and is a general approach for elucidating transient protein surface interactions.

biophysics↗

bioRxiv2018

Loss of mitochondrial SIRT4 shortens lifespan and leads to a decline in physical activity

Mitochondrial mechanisms and pathways have recently emerged as critical determinants of organismal aging. While nuclear sirtuins have been shown to regulate aging, whether mitochondrial sirtuins do so is still unclear. Here, we report that mitochondrial dSirt4 mediates organismal survival. We establish that absence of dSirt4 leads to reduced lifespan independent of dietary inputs. Further by assaying locomotion, a key correlate of aging, we demonstrate that dSirt4 null flies are severely physically impaired with a significant reduction in locomotion. In summary, we report for the first time that mitochondrial dSirt4 is a key determinant of longevity and its loss leads to early aging.

physiology↗

bioRxiv2017

Clearance of senescent decidual cells by uterine natural killer cells drives endometrial remodeling during the window of implantation

In cycling human endometrium, menstruation is followed by rapid estrogen-dependent growth. Upon ovulation, progesterone and rising cellular cAMP levels activate the transcription factor Forkhead box O1 (FOXO1) in endometrial stromal cells (EnSCs), leading to cell cycle exit and differentiation into decidual cells that control embryo implantation. Here we show that FOXO1 also causes acute senescence of a subpopulation of decidualizing EnSCs in an IL-8 dependent manner. Selective depletion or enrichment of this subpopulation revealed that decidual senescence drives the transient inflammatory response associated with endometrial receptivity. Further, senescent cells prevent differentiation of endometrial mesenchymal stem cells in decidualizing cultures. As the cycle progresses, IL-15 activated uterine natural killer (uNK) cells selectively target and clear senescent decidual cells through granule exocytosis. Our findings reveal that acute decidual senescence governs endometrial rejuvenation and remodeling at embryo implantation, and suggest a critical role for uNK cells in maintaining homeostasis in cycling endometrium.

cell biology↗