Alex S. Holehouse

Generative design of functional disordered regions in a developmental transcription factor

The paper designs functional disordered regions in a transcription factor using biophysical principles to predict chromatin binding function.

Proteoform plasticity modulates the temperature response in circadian timekeeping

This study investigates how alternative splicing of intrinsically disordered regions in the fungal circadian protein FRQ affects temperature-dependent clock function.

Lipoproteins modulate the uptake and biological functionof cationic cell-penetrating peptides across the animal lineage.

This study identifies lipoprotein-mediated endocytosis as a conserved mechanism for cationic cell-penetrating peptides across animal lineages, showing it modulates their antimicrobial function.

Combinatorial sequence elements fine-tune mitochondrial protein import to facilitate dual localization

This study identifies sequence elements that enable dual localization of mitochondrial proteins, showing how combinatorial features regulate import and function across compartments.

Subnuclear cofactor partitioning underlies auxin-dependent transcriptional regulation

The paper identifies a biochemical mechanism by which the MpARF1 transcription factor activates gene expression through subnuclear clustering and Mediator complex recruitment, revealing an evolutionary innovation in auxin response.

C9ORF72-derived polyGR polypeptides disrupt passive nucleocytoplasmic transport by tuning protein affinity for the nuclear pore barrier

This study shows how polyGR polypeptides from C9ORF72 disrupt nucleocytoplasmic transport by altering protein affinity for the nuclear pore FG barrier, leading to biphasic transport outcomes and protein aggregation.

Cellular Function of a Biomolecular Condensate Is Determined by Its Ultrastructure

The paper investigates how the ultrastructure of biomolecular condensates, using PopZ as a model, influences their function through molecular interactions and phase-dependent conformational changes.

Direct Optical Quantification of Chain Collapse, Reduced Dielectric, and Water Release Driving Protein Phase Separation

This study quantifies the physical and chemical changes during protein phase separation using optical and spectroscopic methods combined with computational modeling.

The dimerization domain of SARS CoV 2 Nucleocapsid protein is partially disordered as a monomer and forms a high affinity dynamic complex.

This paper quantifies the dimerization mechanisms of SARS-CoV-2 Nucleocapsid protein, showing it forms a high-affinity dynamic complex with a dissociation constant of ~12 nM.

Direct prediction of intermolecular interactions driven by disordered regions

The paper develops a method to predict intermolecular interactions between intrinsically disordered regions and partner proteins using chemical physics principles.

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms

The paper identifies two categories of transcription factor isoforms with distinct molecular functions and shows they contribute to gene regulatory complexity.

Disentangling folding from energetic traps in simulations of disordered proteins

This paper introduces an algorithm to quantify local conformational heterogeneity in protein simulations, distinguishing between well-sampled, poorly-sampled, and folded regions of disordered proteins.

Accurate predictions of conformational ensembles of disordered proteins with STARLING

STARLING predicts conformational ensembles of disordered proteins from sequence, enabling rapid analysis of their structural plasticity and functional implications.

LEA_4 motifs function alone and in conjunction with synergistic cosolutes to protect a labile enzyme during desiccation

This study shows LEA_4 motifs protect an enzyme during desiccation, with enhanced protection when combined with synergistic cosolutes.

Molecular insights into the interaction between a disordered protein and a folded RNA

This study characterizes the RNA-binding properties of a disordered protein, SERF, and shows that binding to RNA causes modest global compaction without inducing structural changes in either molecule.

Phosphorylation of disordered proteins tunes local and global intramolecular interactions

This study uses all-atom simulations to model phosphorylation effects on intrinsically disordered proteins, showing agreement with experimental data on conformational changes.

Metapredict enables accurate disorder prediction across the Tree of Life

Metapredict V3 predicts intrinsically disordered regions across 20,000 proteomes to assess disorder prevalence across life kingdoms.

Mutational scanning of CRX classifies clinical variants and reveals biochemical properties of the transcriptional effector domain

The paper performs a deep mutational scan of CRX variants to classify clinical variants and reveals biochemical properties of the transcriptional effector domain.

High-throughput affinity measurements of direct interactions between activation domains and co-activators

This study quantifies direct interactions between 204 human activation domains and eight co-activators using a microfluidic platform, revealing 334 novel binding pairs and demonstrating the utility of analytical models for predicting activation.

Protein Surface Chemistry Encodes an Adaptive Tolerance to Desiccation

The paper identifies protein surface chemistry as a determinant of desiccation tolerance and shows that modifying surface amino acids can confer tolerance to otherwise sensitive proteins.

Rational protein engineering to enhance MHC-independent T cell receptors

The paper designs MHC-independent T cell receptors (miTCRs) to enhance cancer immunotherapy by improving receptor stability and function through structural modeling and iterative sequence modifications.

Wrapping of single-stranded DNA by Replication Protein A and modulation through phosphorylation

This study uses single-molecule techniques to show that RPA partially wraps ssDNA and that phosphorylation at Ser-384 modulates this wrapping.

Disordered proteins interact with the chemical environment to tune their protective function during drying

This study investigates how disordered proteins interact with endogenous cosolutes during drying to enhance desiccation protection across different organisms.

Structural dynamics of the intrinsically disordered linker region of cardiac troponin T

This paper investigates the structural dynamics of the intrinsically disordered troponin-T linker region using single-molecule FRET, molecular dynamics simulations, and functional assays, showing its dynamic behavior and how a mutation affects intermolecular interactions.

The formation of a fuzzy complex in the negative arm regulates the robustness of the circadian clock.

The paper identifies a fuzzy complex formed by negative-arm proteins that regulates the robustness of the circadian clock through electrostatic interactions and conserved motifs.

Spatial Organization of Gas Vesicles is Governed by Phase-separable GvpU

The paper identifies GvpU as the protein governing gas vesicle clustering and shows how its phase transition behavior modulates cellular fitness and clustering states.

SHEPHARD: a modular and extensible software architecture for analyzing and annotating large protein datasets

SHEPHARD is a software package designed to simplify the integration and analysis of large protein sequence annotations.

Metapredict V2: An update to metapredict, a fast, accurate, and easy-to-use predictor of consensus disorder and structure

metapredict V2 claims better disorder-prediction accuracy than the legacy model, shipping as a web server, Python package and command-line tool, illustrated on human transcription factors.

SWI/SNF senses carbon starvation with a pH-sensitive low complexity sequence

The paper shows that the SWI/SNF complex uses a pH-sensitive low complexity sequence to sense carbon starvation in yeast.

Design principles of acidic transcriptional activation domains

The paper identifies three design principles of acidic transcriptional activation domains through experimental analysis and develops a predictor to identify these domains in the human proteome.