Siddiq, M. | Search bioRxiv

bioRxiv2025

Deep homology and design of proteasome chaperone proteins in Candida auris

A central tenet of biology is that protein structure mediates the sequence-function relationship. Recently, there has been excitement about the promise of advances in protein structure modeling to generate hypotheses about sequence-structure-function relationships based on successes with controlled benchmarks. Here, we leverage structural similarity to identify rapidly evolving proteasome assembly chaperones and characterize their function in the emerging fungal pathogen Candida auris. Despite the large sequence divergence, we demonstrate conservation of structure and function across hundreds of millions of years of evolution, representing a case of rapid neutral evolution. Using the functional constraints on structure from these naturally evolved sequences, we prospectively designed de novo chaperones and demonstrate that these artificial proteins can rescue complex biological processes in the context of the whole cell.

evolutionary biology↗

bioRxiv2017

Dynamic balance between vesicle transport and microtubule growth enables neurite growth

Whole cell responses involve multiple subcellular processes (SCPs). To understand how balance between SCPs controls the dynamics of whole cell responses we studied neurite outgrowth in rat primary cortical neurons in culture. We used a combination of dynamical models and experiments to understand the conditions that permitted growth at a specified velocity and when aberrant growth could lead to the formation of dystrophic bulbs. We hypothesized that dystrophic bulb formation is due to quantitative imbalances between SCPs. Simulations predict redundancies between lower level sibling SCPs within each type of high level SCP. In contrast, higher level SCPs, such as vesicle transport and exocytosis or microtubule growth characteristic of each type need to be strictly coordinated with each other and imbalances result in stalling of neurite outgrowth. From these simulations, we predicted the effect of changing the activities of SCPs involved in vesicle exocytosis or microtubule growth could lead to formation of dystrophic bulbs. siRNA ablation experiments verified these predictions. We conclude that whole cell dynamics requires balance between the higher-level SCPs involved and imbalances can terminate whole cell responses such as neurite outgrowth.

systems biology↗