Biology subjects

Mallela, A.

Publications and source records attributed to Mallela, A..

3 recordsLinked to original sources

bioRxiv2025

Structural hormesis in protein aggregation: A minimal mechanistic model

Protein aggregation underlies the pathogenesis of many neurodegenerative diseases, and inhibitors are often assumed to elicit monotonic dose-responses. We ask whether simple aggregation pathways can intrinsically generate hormesis--a biphasic profile with low-dose stimulation and high-dose inhibition. We formulate a minimal mechanistic model in which a single inhibitor interacts sequentially with pathway intermediates. Analysis and simulation show a robust non-monotonic response: low inhibitor doses increase aggregate formation, whereas high doses suppress it. We prove that this profile is structural--arising from chemical network topology rather than tuned kinetic parameters. The mechanism rationalizes pro-aggregating effects at low doses and underscores the need for full-range dose-response evaluation in inhibitor screening.

pharmacology and toxicology↗

bioRxiv2019

Robustness and the evolution of length control strategies in the type III secretion system and flagellar hook

Bacteria construct many structures, like the flagellar hook and the type III secretion system, that aid in crucial processes such as locomotion and pathogenesis. Experimental work has suggested two competing mechanisms bacteria could use to regulate length in these structures: the \"ruler\" mechanism and the \"substrate switching\" mechanism. In this work, we constructed a mathematical model of length control based on the ruler mechanism, and found that the predictions of this model are consistent with experimental data not just for the scaling of the average length with the ruler protein length, but also the variance. Interestingly, we found that the ruler mechanism allows for the evolution of needles with large average lengths without the concomitant large increase in variance that occurs in the substrate switching mechanism. These findings shed new light on the trade-offs that may have lead to the evolution of different length control mechanisms in different bacterial species.

biophysics↗

bioRxiv2019

Crosstalk and Ultrasensitivity in Protein Degradation Pathways

Protein turnover is vital to protein homeostasis within the cell. Many proteins are degraded efficiently only after they have been post-translationally \"tagged\" with a polyubiquitin chain. Ubiquitylation is a form of Post-Translational Modification (PTM): addition of a ubiquitin to the chain is catalyzed by E3 ligases, and removal of ubiquitin is catalyzed by a De-UBiquitylating enzyme (DUB). Over three decades ago, Goldbeter and Koshland discovered that reversible PTM cycles function like on-off switches when the substrates are at saturating concentrations. Although this finding has had profound implications for the understanding of switch-like behavior in biochemical networks, the general behavior of PTM cycles subject to synthesis and degradation has not been studied. Using a mathematical modeling approach, we found that simply introducing protein turnover to a standard modification cycle has profound effects, including significantly reducing the switch-like nature of the response. Our findings suggest that many classic results on PTM cycles may not hold in vivo where protein turnover is ubiquitous. We also found that proteins sharing an E3 ligase can have closely related changes in their expression levels. These results imply that it may be difficult to interpret experimental results obtained from either overexpressing or knocking down protein levels, since changes in protein expression can be coupled via E3 ligase crosstalk. Understanding crosstalk and competition for E3 ligases will be key to ultimately developing a global picture of protein homeostasis.

systems biology↗