Biology subjects

Scholl, D.

Publications and source records attributed to Scholl, D..

4 recordsLinked to original sources

bioRxiv2026

From Hummingbird to Elephant: Amyloid Formation in Natural Transthyretin Variants

Transthyretin (TTR) is a secreted protein associated with cardiac and other amyloid diseases via misfolding. We have previously shown that agitation of human TTR solutions at neutral pH results in aggregation and fibril formation. Here we report that agitation-induced aggregation of TTR from species with very different heart rates (Annas hummingbird, hbTTR, and African elephant, aeTTR) differs from that of human TTR (huTTR). Aggregation of hbTTR is slow and favors formation of smaller, fibrillar aggregates, while aeTTR aggregation is rapid and favors larger, more amorphous particles. Spherical, early-stage oligomeric intermediates were found for all variants by mass photometry and electron microscopy. The slow aggregation of hbTTR matches its resistance to denaturation by 8 M urea. The widely different aggregation behavior exhibited by these naturally occurring TTR variants in response to mechanical agitation under close to physiological conditions provides insight into how small sequence differences can contribute to the evolutionary fitness of different animals.

biophysics↗

bioRxiv2024

Cellular Function of a Biomolecular Condensate Is Determined by Its Ultrastructure

Biomolecular condensates play key roles in the spatiotemporal regulation of cellular processes. Yet, the relationship between atomic features and condensate function remains poorly understood. We studied this relationship using the polar organizing protein Z (PopZ) as a model system, revealing how its material properties and cellular function depend on its ultrastructure. We revealed PopZs hierarchical assembly into a filamentous condensate by integrating cryo-electron tomography, biochemistry, single-molecule techniques, and molecular dynamics simulations. The helical domain drives filamentation and condensation, while the disordered domain inhibits them. Phase-dependent conformational changes prevent interfilament contacts in the dilute phase and expose client binding sites in the dense phase. These findings establish a multiscale framework that links molecular interactions and condensate ultrastructure to macroscopic material properties that drive cellular function.

cell biology↗

bioRxiv2022

Structural basis of interdomain communication in PPARγ

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates transcription via two activation function (AF) regulatory domains: a ligand-dependent AF-2 coregulator interaction surface within the C-terminal ligand-binding domain (LBD), and an N-terminal disordered AF-1 domain (NTD or A/B region) that functions through poorly understood structural mechanisms. Here, we show the PPAR{gamma} AF-1 contains an evolutionary conserved Trp-Pro motif that undergoes cis/trans isomerization, populating two long-lived conformations that participate in intradomain AF-1 and interdomain interactions including two surfaces in the C-terminal LBD ({beta}-sheet and the AF-2 surface), which are predicted in AlphaFold 3 models but not AlphaFold 2. NMR and chemical crosslinking mass spectrometry show that interdomain interactions occur for soluble isolated AF-1 and LBD proteins, as well as in full-length PPAR{gamma} in a phase separated state. Mutation of the region containing the Trp-Pro motif, which abrogates cis/trans isomerization of this region, impacts LBD interaction and reduces basal PPAR{gamma}-mediated transcription and agonist-dependent activation of PPAR{gamma}. Our findings provide structural insight into published in vitro and cellular studies that reported interdomain functional communication between the PPAR{gamma} AF-1 and LBD suggesting some of these effects may be mediated via AF-1/LBD interactions.

biochemistry↗

bioRxiv2019

Nucleotide-mediated allosteric regulation of bifunctional Rel enzymes

Bifunctional Rel stringent factors, the most broadly distributed class of RSHs, are ribosome-associated enzymes that transfer a pyrophosphate group from ATP onto the 3' of GTP or GDP to synthesize (p)ppGpp and also catalyse the 3' pyrophosphate hydrolysis of the alarmone to degrade it. The precise regulation of these enzymes seems to be a complex allosteric mechanism, and despite decades of research, it is unclear how the two opposing activities of Rel are controlled at the molecular level. Here we show that a stretch/recoil guanosine-switch mechanism controls the catalytic cycle of T. thermophilus Rel (RelTf). The binding of GDP/ATP stretches apart the NTD catalytic domains of RelTf (RelTtNTD) activating the synthetase domain and allosterically blocking the hydrolase active site. Conversely, binding of ppGpp unlocks the hydrolase domain and triggers recoil of both NTDs, which partially buries the synthetase active site and precludes the binding of synthesis precursors. This allosteric mechanism acts as an activity switch preventing futile cycles of alarmone synthesis and degradation.

molecular biology↗