Biology subjects

Zhao, V.

Publications and source records attributed to Zhao, V..

4 recordsLinked to original sources

bioRxiv2026

Microtubule Lattice Spacing Governs MAP-Motor Regulation

Microtubules (MTs) serve as intracellular tracks that enable molecular motors to transport cargos to specific cellular destinations. It has been proposed that the signals directing motor-driven transport are encoded on MTs through different isotypes, lattice conformations, and post- translational modifications (PTMs) of tubulin, or MT-associated proteins (MAPs) that decorate the MT surface. However, molecular predictions of these models have not been rigorously tested in vitro. Using isotypically pure recombinant tubulin and biochemical reconstitution, we examined how tubulin PTMs and MT lattice spacing influence MAP binding and kinesin-1 motility. We found that kinesin-1 is largely insensitive to tubulin PTMs but is strongly regulated by MT lattice spacing. Likewise, the MAPs tau, MAP7, MAP4, DCX, and MAP9 exhibit little sensitivity to tubulin PTMs, whereas the MT-binding affinities of tau, DCX, and MAP7 depend on lattice spacing. In the presence of activating (MAP7) and inhibitory (tau) MAPs, lattice spacing determines MAP occupancy and thereby controls kinesin-1 motility. These findings support a two-layer transport code in which MT lattice spacing directs MAP binding, and MAPs determine which motors can move along individual MT tracks.

biochemistry↗

bioRxiv2026

Linked origins but distinct roles for extreme length and sequence variation at a tandem repeat in CACNA1C

Length variation in tandem repeats is a well-established driver of disease risk and is commonly assumed to arise from persistent genomic instability. Here, we characterize TRACT, a 30-bp variable number tandem repeat (VNTR) intronic to the calcium channel gene CACNA1C. TRACT exhibits extreme length variation (3-30+ kb) and has been previously linked to risk for bipolar disorder and schizophrenia. By examining multiple human cohorts, we find that TRACT alleles are strikingly bimodal in both length and sequence composition. Short alleles (TRACTS, [~]6 kb) and long alleles (TRACTL, [~]24 kb) are enriched for distinct 30-bp variants and are found on separate haplotypes that arose prior to the human migration out of Africa. Our data suggest that these ancient alleles expanded via perfect repeat tracts that were disrupted by accumulated mutations to result in relative length stability in extant humans, where there is no evidence for overt germline or somatic instability. Interestingly, neuropsychiatric disease risk is associated with specific 30-bp variants within TRACTS alleles, but not with overall TRACT length or with 30-bp variants enriched in TRACTL alleles. Instead, TRACTL alleles are associated with decreased gene expression in fibroblasts and testis. Together, these findings motivate joint examination of both sequence composition and length variation to fully understand the effects of VNTRs on evolution, trait variation, and disease risk.

genetics↗

bioRxiv2024

e3SIM: epidemiological-ecological-evolutionary simulation framework for genomic epidemiology

Infectious disease dynamics are driven by the complex interplay of epidemiological, ecological, and evolutionary processes. Accurately modeling these interactions is crucial for understanding pathogen spread and informing public health strategies. However, existing simulators often fail to capture the dynamic interplay between these processes, resulting in oversimplified models that do not fully reflect real-world complexities in which the pathogens genetic evolution dynamically influences disease transmission. We introduce the epidemiological-ecological-evolutionary simulator (e3SIM), an open-source framework that concurrently models the transmission dynamics and molecular evolution of pathogens within a host population while integrating environmental factors. Using an agent-based, discrete-generation, forward-in-time approach, e3SIM incorporates compartmental models, host-population contact networks, and quantitative-trait models for pathogens. This integration allows for realistic simulations of disease spread and pathogen evolution. Key features include a modular and scalable design, flexibility in modeling various epidemiological and population-genetic complexities, incorporation of time-varying environmental factors, and a user-friendly graphical interface. We demonstrate e3SIMs capabilities through simulations of realistic outbreak scenarios with SARS-CoV-2 and Mycobacterium tuberculosis, illustrating its flexibility for studying the genomic epidemiology of diverse pathogen types.

bioinformatics↗

bioRxiv2020

Effect of protein structure on evolution of cotranslational folding

Cotranslational folding is expected to occur when the folding speed of the nascent chain is faster than the translation speed of the ribosome, but it is difficult to predict which proteins cotranslationally fold. Here, we simulate evolution of model proteins to investigate how native structure influences evolution of cotranslational folding. We developed a model that connects protein folding during and after translation to cellular fitness. Model proteins evolved improved folding speed and stability, with proteins adopting one of two strategies for folding quickly. Low contact order proteins evolve to fold cotranslationally. Such proteins adopt native conformations early on during the translation process, with each subsequently translated residue establishing additional native contacts. On the other hand, high contact order proteins tend not to be stable in their native conformations until the full chain is nearly extruded. We also simulated evolution of slowly translating codons, finding that slowing translation at certain positions enhances cotranslational folding. Finally, we investigated real protein structures using a previously published dataset that identified evolutionarily conserved rare codons in E. coli genes and associated such codons with cotranslational folding intermediates. We found that protein substructures preceding conserved rare codons tend to have lower contact orders, in line with our finding that lower contact order proteins are more likely to fold cotranslationally. Our work shows how evolutionary selection pressure can cause proteins with local contact topologies to evolve cotranslational folding. Statement of significanceSubstantial evidence exists for proteins folding as they are translated by the ribosome. Here we developed a biologically intuitive evolutionary model to show that avoiding premature protein degradation can be a sufficient evolutionary force to drive evolution of cotranslational folding. Furthermore, we find that whether a proteins native fold consists of more local or more nonlocal contacts affects whether cotranslational folding evolves. Proteins with local contact topologies are more likely to evolve cotranslational folding through nonsynonymous mutations that strengthen native contacts as well as through synonymous mutations that provide sufficient time for cotranslational folding intermediates to form.

biophysics↗