Amino acid sequence encodes protein abundance shaped by protein stability at reduced synthesis cost DOI Creative Commons
Filip Buric, Sandra Viknander, Xiaozhi Fu

и другие.

Protein Science, Год журнала: 2024, Номер 34(1)

Опубликована: Дек. 12, 2024

Abstract Understanding what drives protein abundance is essential to biology, medicine, and biotechnology. Driven by evolutionary selection, an amino acid sequence tailored meet the required of a proteome, underscoring intricate relationship between functional demand. Yet, specific role sequences in determining proteome remains elusive. Here we show that alone encodes over half variation across all domains life, ranging from bacteria mouse human. With attempt go beyond predictions, trained manageable‐size Transformer model interpret latent factors predictive abundances. Intuitively, model's attention focused on protein's structural features linked stability metabolic costs related synthesis. To probe these relationships, introduce MGEM (Mutation Guided Embedded Manifold), methodology for guiding through modifications. We find mutations which increase predicted have significantly altered polarity hydrophobicity, connection abundance. Through molecular dynamics simulations revealed abundance‐enhancing possibly contribute thermostability increasing rigidity, occurs at lower synthesis cost.

Язык: Английский

The genetic architecture of protein stability DOI Creative Commons
André J. Faure, Aina Martí-Aranda, Cristina Hidalgo-Carcedo

и другие.

Nature, Год журнала: 2024, Номер unknown

Опубликована: Сен. 25, 2024

Язык: Английский

Процитировано

14
Pervasive mislocalization of pathogenic coding variants underlying human disorders DOI
Jessica Lacoste,

Marzieh Haghighi,

Shahan Haider

и другие.

Cell, Год журнала: 2024, Номер 187(23), С. 6725 - 6741.e13

Опубликована: Сен. 30, 2024

Язык: Английский

Процитировано

11
Genetics, energetics and allostery during a billion years of hydrophobic protein core evolution DOI Creative Commons
Albert Escobedo,

Gesa Voigt,

André J. Faure

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 12, 2024

Abstract Protein folding is driven by the burial of hydrophobic amino acids in a tightly-packed core that excludes water. The genetics, biophysics and evolution cores are not well understood, part because lack systematic experimental data on sequence combinations do - constitute stable functional cores. Here we randomize protein evaluate their stability function at scale. show vast numbers acid can but these alternative frequently disrupt allosteric effects. These strong effects due to complicated, highly epistatic fitness landscapes rather, pervasive nature allostery, with many individually small energy changes combining function. Indeed both ligand binding be accurately predicted over very large evolutionary distances using additive models contribution from pairwise energetic couplings. As result, trained one predict across hundreds millions years evolution, only rare couplings experimentally identify limiting transplantation between diverged proteins. Our results reveal simple architecture suggest allostery major constraint evolution.

Язык: Английский

Процитировано

3
Revolutionizing large-scale DNA synthesis with microchip-based massive in parallel synthesis system DOI Creative Commons
Xiandi Zhang, X. L. Jiang, Yun Wang

и другие.

Опубликована: Окт. 31, 2024

Abstract DNA synthesis serves as the fundamental enabling technology of engineering biology, aiming to provide molecules designed composition, length, and complexity at scale low cost. Current high-throughput technologies rely on intricate chip manufacturing microfluidic systems large-scale synthetic oligonucleotides, expense concentration limited compatibility in processing longer constructs assembly. Here, we report a microchip-based massive parallel (mMPS), pioneering an “identification-sorting-synthesis-recycling” iteration mechanism microchips for high throughput synthesis. In comparison microarray-based methods, demonstrate that our method can increase product by 4 magnitudes (to picomole-scale per sequence) greatly simplifies downstream processes gene construction. By construction 1.97 million-diversity variant libraries cover 1,254 human protein domains, demonstrated uniformity constructed using mMPS-derived oligos is improved, with amino acid distribution highly consistent designed. addition, synthesizing 285 1kb-to-3kb genes varying degrees sequence from previously reported strains A501 3DAC, potential ancestor early archaea bacteria, result shows overall assembly success rate increased 10-fold other methods. Our mMPS holds close gap between quality cost writing increasing demand across many sectors research industrial activities.

Язык: Английский

Процитировано

2
Energetic portrait of the amyloid beta nucleation transition state DOI Creative Commons
Anna Arutyunyan, Mireia Seuma, André J. Faure

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

Amyloid protein aggregates are pathological hallmarks of more than fifty human diseases but how soluble proteins nucleate to form amyloids is poorly understood. Here we use combinatorial mutagenesis, a kinetic selection assay, and machine learning massively perturb the energetics nucleation reaction amyloid beta (Aβ42), that in Alzheimer's disease. In total, quantify rates >140,000 variants Aβ42. This allows us accurately changes activation energy for all possible amino acid substitutions first time and, addition, >600 energetic interactions between mutations. The data reveal simple interpretable genetic architecture an reaction. Strikingly, strong couplings rare identify subset structural contacts mature fibrils. Together with changes, this strongly suggests Aβ42 transition state structured short C-terminal region, providing model may initiate We believe approach can be widely applied probe structures reactions.

Язык: Английский

Процитировано

0
Protein structural context of cancer mutations reveals molecular mechanisms and candidate driver genes DOI Creative Commons

Diego Chillón-Pino,

Mihaly Badonyi, Colin A. Semple

и другие.

Cell Reports, Год журнала: 2024, Номер 43(11), С. 114905 - 114905

Опубликована: Окт. 22, 2024

Язык: Английский

Процитировано

0
A pharmacological chaperone stabilizer rescues the expression of the vast majority of pathogenic variants in a G protein-coupled receptor DOI Creative Commons
Taylor L. Mighell, Ben Lehner

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 29, 2024

Abstract Reduced protein stability is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating destabilizing pharmacological chaperones (PCs, also known as correctors or stabilizers), small molecules that bind to and stabilize target proteins. PCs have been approved clinical treatments specific variants, but energetics suggest their effects might be much more general. Here, we test this hypothesis first time comprehensively quantifying PC efficacy all in a human disease gene, vasopressin 2 receptor (V2R), G-protein coupled loss-of-function nephrogenic diabetes insipidus (NDI). Strikingly, treatment with rescues expression of nearly destabilized non-rescued identifying drug’s binding site. Our results provide proof-of-principle single molecule can rescue throughout protein’s structure. The application principle other proteins should allow development effective therapies many genetic diseases.

Язык: Английский

Процитировано

0
Amino acid sequence encodes protein abundance shaped by protein stability at reduced synthesis cost DOI Creative Commons
Filip Buric, Sandra Viknander, Xiaozhi Fu

и другие.

Protein Science, Год журнала: 2024, Номер 34(1)

Опубликована: Дек. 12, 2024

Abstract Understanding what drives protein abundance is essential to biology, medicine, and biotechnology. Driven by evolutionary selection, an amino acid sequence tailored meet the required of a proteome, underscoring intricate relationship between functional demand. Yet, specific role sequences in determining proteome remains elusive. Here we show that alone encodes over half variation across all domains life, ranging from bacteria mouse human. With attempt go beyond predictions, trained manageable‐size Transformer model interpret latent factors predictive abundances. Intuitively, model's attention focused on protein's structural features linked stability metabolic costs related synthesis. To probe these relationships, introduce MGEM (Mutation Guided Embedded Manifold), methodology for guiding through modifications. We find mutations which increase predicted have significantly altered polarity hydrophobicity, connection abundance. Through molecular dynamics simulations revealed abundance‐enhancing possibly contribute thermostability increasing rigidity, occurs at lower synthesis cost.

Язык: Английский

Процитировано

0