Surface delivery quantification reveals distinct trafficking efficiencies among clustered protocadherin isoforms DOI Creative Commons
Elizabeth May, Rachelle Gaudet

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

Опубликована: Сен. 24, 2024

Abstract Proteins that transmit molecules and signals across the plasma membrane are crucial in cell biology because they enable cells to sense respond their surroundings. A major challenge for studying cell-surface proteins is often do not fold or traffic properly when produced heterologous cells. We developed a strategy quantifying surface localization from fluorescence microscopy images of surface-stained Using clustered protocadherins, protein family important cell-cell recognition during neuronal development, as model system, we found delivery levels vary among protocadherin isoforms between wildtype engineered variants. Quantifying these differences provides evidence challenges generally accepted hypothesis cis dimerization controls protocadherins. This work establishes generalizable framework screening variants interest proper localization. Significance Surface allow interact with environments, activities regulated by removal membrane. quantitatively compare based on established epitope tag-based staining methods. natural essential neuron show such quantitative comparisons trafficking facilitate interpretation mutational effects can shed light key regulatory mechanisms. find differ that, contrary what was previously thought, domain inhibits some protocadherins may so independently its protein-protein interaction interface.

Язык: Английский

Molecular basis of proton sensing by G protein-coupled receptors DOI
Matthew K. Howard, Nick Hoppe, Xi‐Ping Huang

и другие.

Cell, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

9
Site-saturation mutagenesis of 500 human protein domains DOI Creative Commons

Antoni Beltran,

Xuege Jiang, Yue Shen

и другие.

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 8, 2025

Abstract Missense variants that change the amino acid sequences of proteins cause one-third human genetic diseases 1 . Tens millions missense exist in current population, and vast majority these have unknown functional consequences. Here we present a large-scale experimental analysis across many different proteins. Using DNA synthesis cellular selection experiments quantify effect more than 500,000 on abundance 500 protein domains. This dataset reveals 60% pathogenic reduce stability. The contribution stability to fitness varies is particularly important recessive disorders. We combine measurements with language models annotate sites Mutational effects are largely conserved homologous domains, enabling accurate prediction entire families using energy models. Our data demonstrate feasibility assaying at scale provides large consistent reference for clinical variant interpretation training benchmarking computational methods.

Язык: Английский

Процитировано

6
Transport mechanism and structural pharmacology of human urate transporter URAT1 DOI Creative Commons
Yaxin Dai, Chia‐Hsueh Lee

Cell Research, Год журнала: 2024, Номер unknown

Опубликована: Сен. 9, 2024

Язык: Английский

Процитировано

15
Two heads are better than one: Unravelling the potential Impact of Artificial Intelligence in nanotechnology DOI Creative Commons
Gaurav Gopal Naik,

Vijay A. Jagtap

Nano TransMed, Год журнала: 2024, Номер 3, С. 100041 - 100041

Опубликована: Июль 9, 2024

Artificial Intelligence (AI) and Nanotechnology are two cutting-edge fields that hold immense promise for revolutionizing various aspects of science, technology, everyday life. This review delves into the intersection these disciplines, highlighting synergistic relationship between AI Nanotechnology. It explores how techniques such as machine learning, deep neural networks being employed to enhance efficiency, precision, scalability nanotechnology applications. Furthermore, it discusses challenges, opportunities, future prospects integrating with nanotechnology, paving way transformative advancements in diverse domains ranging from healthcare materials science environmental sustainability beyond.

Язык: Английский

Процитировано

10
Deep indel mutagenesis reveals the impact of amino acid insertions and deletions on protein stability and function DOI Creative Commons
Magdalena Topolska,

Antoni Beltran,

Ben Lehner

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 17, 2025

Amino acid insertions and deletions (indels) are an abundant class of genetic variants. However, compared to substitutions, the effects indels on protein stability not well understood. To better understand here we analyse new existing large-scale deep indel mutagenesis (DIM) structurally diverse proteins. The vary extensively among within proteins predicted by computational methods. address this shortcoming present INDELi, a series models that combine experimental or substitution secondary structure information provide good prediction both pathogenicity. Moreover, quantifying protein-protein interactions suggests can be important gain-of-function Our results overview impact method predict their genome-wide. understood poorly predicted. Here, authors perform experiments amino

Язык: Английский

Процитировано

1
Understanding, inhibiting, and engineering membrane transporters with high-throughput mutational screens DOI
Steven T. Miller, Christian B. Macdonald, Srivatsan Raman

и другие.

Cell chemical biology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

1
Site saturation mutagenesis of 500 human protein domains reveals the contribution of protein destabilization to genetic disease DOI Creative Commons

Antoni Beltran,

Xuege Jiang, Yue Shen

и другие.

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

Опубликована: Апрель 29, 2024

Abstract Missense variants that change the amino acid sequences of proteins cause one third human genetic diseases 1 . Tens millions missense exist in current population, with vast majority having unknown functional consequences. Here we present first large-scale experimental analysis across many different proteins. Using DNA synthesis and cellular selection experiments quantify impact >500,000 on abundance >500 protein domains. This dataset, Human Domainome 1, reveals >60% pathogenic reduce stability. The contribution stability to fitness varies diseases, is particularly important recessive disorders. Combining measurements language models annotates sites Mutational effects are largely conserved homologous domains, allowing accurate prediction entire families using energy models. demonstrates feasibility assaying at scale provides a large consistent reference dataset for clinical variant interpretation training benchmarking computational methods.

Язык: Английский

Процитировано

8
Rare Diseases Linked to Mutations in Vitamin Transporters Expressed in the Human Blood–Brain Barrier DOI
Sook Wah Yee,

Joanne Wang,

Kathleen M. Giacomini

и другие.

Clinical Pharmacology & Therapeutics, Год журнала: 2024, Номер unknown

Опубликована: Сен. 5, 2024

Recent advances have significantly enhanced our understanding of the role membrane transporters in drug disposition, particularly focusing on their influence pharmacokinetics, and consequently, pharmacodynamics. The relevance these clinical pharmacology is well acknowledged. research has also underscored critical as targets human diseases, including involvement rare genetic disorders. This review focuses for water‐soluble B vitamins, such thiamine, riboflavin, biotin, essential cofactors metabolic enzymes. Mutations transporters, SLC19A3 (thiamine), SLC52A2, SLC52A3 (riboflavin), SLC5A6 (multiple vitamins pantothenic acid biotin) are linked to severe neurological disorders due blood–brain barrier, which crucial brain vitamin supply. Current treatments, mainly involving supplementation, often result variable response. provides a short perspective blood‐cerebrospinal fluid barrier highlights potential development pharmacologic treatments associated with mutations transporters.

Язык: Английский

Процитировано

3
SLCO1B1 Functional Variants, Bilirubin, Statin‐Induced Myotoxicity, and Recent Sub‐Saharan African Ancestry: A Precision Medicine Health Equity Study DOI Creative Commons
Tanushree Haldar, Mark Kvale, Jia Yang

и другие.

Clinical Pharmacology & Therapeutics, Год журнала: 2025, Номер unknown

Опубликована: Март 6, 2025

Statin pharmacogenetic implementation guidelines are derived from evidence of primarily Eurocentrically biased study populations. Functional SLCO1B1 variants that rare in these populations have not been equitably investigated and thus missing guidelines. The objective this precision medicine health equity was to determine the clinical validity understudied candidate functional common people with 1,000 Genomes sub-Saharan African superpopulation (1KG-AFR-like) genetic similarity. We conducted our analyses using real-world participants three large, electronic record-linked biobanks. used bilirubin levels (as an endogenous substrate organic anion transporting polypeptide [OATP1B1] function) severe statin-induced myotoxicity phenotypes. Loss-of-function splice variant rs77271279 (P = 1.1 × 10-17) had strongest association elevated total Black (mean 84% AFR-like similarity) followed by missense rs59502379 7.4 10-12) then rs4149056 6.0 10-5). In exploratory subset population who statins (n 77 cases), (odds ratio [OR] 2.85, 95% confidence interval [CI] 1.08-7.52), but (OR 1.75, CI 0.62-4.73) associated myotoxicity. Sensitivity >5% similarity corroborated findings. For white participants, were precluding subsequent analyses. Our findings highlight relevance for on testing panels a potential immediate impact reducing risk patients, group historically excluded genomic research. Future studies require larger statin user less heterogeneity type.

Язык: Английский

Процитировано

0
Energetic and structural control of polyspecificity in a multidrug transporter DOI Creative Commons
Steven T. Miller, Katherine A. Henzler‐Wildman, Srivatsan Raman

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 10, 2025

Abstract Multidrug efflux pumps are dynamic molecular machines that drive antibiotic resistance by harnessing ion gradients to export chemically diverse substrates. Despite their clinical importance, the principles underlying multidrug promiscuity and energy efficiency remain poorly understood. Using multiparametric deep mutational scanning across eight substrates two conditions, we deconvolute contributions of substrate recognition, energetic coupling, protein stability, providing an integrated, high-resolution view transport. We find specificity arises from a distributed network residues extending beyond binding site, with mutations reshape binding, conformational flexibility, membrane interactions. Further, apply pH-based selection scheme measure effect mutation on pH-dependent transport efficiency. By integrating these data, reveal fundamental relationship between promiscuity: highly efficient variants exhibit broad profiles, while inefficient narrower. These findings establish direct link coupling polyspecificity, uncovering biochemical logic

Язык: Английский

Процитировано

0