Date of this Version
Fay, J. 2022. The Crucial Role of Sestrins in Oxidative Stress Response and Disease: An Analysis of Phosphorylation Mutation S110A in hSesn2. Undergraduate Honors thesis, University of Nebraska-Lincoln.
Sestrins are highly conserved proteins which are induced under environmentally stressful conditions to adjust the cell’s response to such disturbances. This protein possesses two domains critical for its dual function in reducing reactive oxygen species (ROS) and regulating the mTORC1 complex. Sestrins may use diverse transcription factors, such as Nrf2, peroxiredoxin reductase activity, and a catalytic cysteine to regenerate oxidized species; however this was confirmed to be through a mechanism likely different than AhpD, for which there was distance sequence similarity. Furthermore, Sestrins are important regulators of TORC1 and AMPK, which are crucial energy sensors able to control cellular metabolism under oxidative stress. Additionally, the role and relative abundance of leucine in relation to the association between Sestrin, GATOR2, and mTORC1 along with Sestrin2 phosphorylation state is further explored and connected to obesity and degenerative diseases. Following literature review, residues Cys125, Leu261, Asp406, Asp407, were identified to be critical for the aforementioned functions of Sestrins when confronted with oxidative stresses. The previously established phosphorylation mutations at position 73, 110, and 254, specifically the mutation of serine to alanine at position 110 (S110A), were analyzed using ChimeraX to determine effects on distance change and how this may alter enzymatic functionality.