Biology subjects

Haller, P.

Publications and source records attributed to Haller, P..

4 recordsLinked to original sources

bioRxiv2025

Structural Mechanism of Prestin-Membrane Mechanotransduction

Sound frequency discrimination in mammals depends on the conformational transitions of prestin (SLC26A5), the piezoelectric motor in outer hair cells. The mechanism that enables prestins electrically driven interconversion and its dependence on membrane mechanics, remains unresolved. Here, we show that membrane forces represent a strong driver of the same conformational changes generated by transmembrane voltage and stabilized by bound anions. Single particle cryo-EM structures of nanodisc-reconstituted prestin were obtained from varying lipid composition and membrane thickness. These structures show that membrane thinning biases prestin from a compact conformation to a fully expanded conformation, mimicking outer hair cell elongation/contraction during electromotility. In contrast, zebrafish SLC26A5 transporters undergo complete elevator movements with redistribution of areal changes across leaflets. The structures, together with mutagenesis, H/D exchange mass spectrometry data, and NLC measurements, offer a high-resolution understanding of how prestin translates membrane tension into charge and motor movement during sound-evoked vibrations, revealing a process of reciprocal electro-mechanical transduction essential for tuning cochlear amplification.

biophysics↗

bioRxiv2023

Neural representation of association strength and prediction error during novel symbol-speech sounds learning

Efficient learning of letters-speech sound associations leads to specialization of visual and audiovisual brain regions and is necessary to develop adequate reading skills. We still do not understand the brain dynamics of this learning process, and the involvement of learning and performance monitoring networks is still underexplored. Here we examined a feedback learning task with two mutually dependent parts in which novel symbol-speech sound associations were learned by 39 healthy adults. We used functional magnetic resonance (fMRI) and a reinforcement learning drift diffusion model that described learning across trials. The model-based analysis showed that posterior-occipital activations during stimulus processing were positively modulated by the trial-by-trial learning, described by the increase in association strength of each audiovisual pair. Prediction errors, describing the update mechanism to learn with feedback across trials, modulated activations in several mid-frontal, striatal and cingulate regions. The two task parts yielded a similar pattern of results although they varied in their relative difficulty. This study demonstrates which processes during audiovisual learning contribute to the rapid visual specialization within an experimental session and delineates a set of coactivated regions engaged in learning from feedback. Our paradigm provides a framework to advance our understanding of the neurobiology of learning and reading development.

neuroscience↗

bioRxiv2023

Folding of Prestin's Anion-Binding Site and the Mechanism of Outer Hair Cell Electromotility

Prestin responds to transmembrane voltage fluctuations by changing its cross-sectional area, a process underlying the electromotility of outer hair cells and cochlear amplification. Prestin belongs to the SLC26 family of anion transporters yet is the only member capable of displaying electromotility. Prestins voltage-dependent conformational changes are driven by the putative displacement of residue R399 and a set of sparse charged residues within the transmembrane domain, following the binding of a Cl- anion at a conserved binding site formed by amino termini of the TM3 and TM10 helices. However, a major conundrum arises as to how an anion that binds in proximity to a positive charge (R399), can promote the voltage sensitivity of prestin. Using hydrogen-deuterium exchange mass spectrometry, we find that prestin displays an unstable anion-binding site, where folding of the amino termini of TM3 and TM10 is coupled to Cl- binding. This event shortens the TM3-TM10 electrostatic gap, thereby connecting the two helices, resulting in reduced cross-sectional area. These folding events upon anion-binding are absent in SLC26A9, a non-electromotile transporter closely related to prestin. Dynamics of prestin embedded in a lipid bilayer closely match that in detergent micelle, except for a destabilized lipid-facing helix TM6 that is critical to prestins mechanical expansion. We observe helix fraying at prestins anion-binding site but cooperative unfolding of multiple lipid-facing helices, features that may promote prestins fast electromechanical rearrangements. These results highlight a novel role of the folding equilibrium of the anion-binding site, and helps define prestins unique voltage-sensing mechanism and electromotility.

biophysics↗

bioRxiv2021

The Orb6-Sts5 Axis Regulates Stress Granule Formation and Heat Stress Response in Fission Yeast

Cellular response to environmental fluctuations, such as increased temperature, is crucial in promoting cell survival and plays an increasingly recognized role in cancer biology. Important cellular functions altered by heat stress are cell polarization and protein translation. Previous studies have shown that heat stress alters the dynamics of Cdc42, a key regulator of cell polarization in eukaryotes, and promotes RNP granule formation, reprogramming protein translation. The biological mechanisms underlying these vast changes are only partially known. Here, we report that conserved NDR kinase Orb6, a homologue of mammalian STK38, responds to heat stress and regulates heat stress resilience by modulating Cdc42 dynamics and promoting stress granule assembly. Also, we discovered a finely tuned mechanism whereby stress-activated MAP kinase Sty1 negatively regulates Orb6 kinase and Orb6 C-terminal phosphorylation during heat stress. Orb6 inhibition by Sty1 increases the sensitivity of the cell to heat stress in a temperature-specific manner, fostering increased stress resilience and metabolic adaptation. These observations highlight the role of NDR kinase in the process of heat adaptation and thermotolerance during environmental cell exposure to elevated temperatures. Summary statementNuclear Dbf2-related kinase Orb6 inhibition by stress-activated protein kinase Sty1 promotes heat stress resilience in a temperature specific manner.

cell biology↗