Ribosome Newsletter: Navigating the Convergence of Proteomics, AI, Synthetic Biology, and Translational Medicine
Welcome to this week's edition of Ribosome! This week, we spotlight discoveries from a diverse array of scientific inquiries, ranging from groundbreaking proteomic studies in Parkinson's disease to crucial advancements in lung adenocarcinoma treatment and biomarkers for predicting suicide attempts. Additionally, we uncover the latest in protein structure prediction and the fascinating world of protein homo-oligomerization, revealing key insights into the structural dynamics that underpin health and disease. Furthermore, we spotlight significant industry movements, including Novartis's strategic acquisition of MorphoSys and Bruker's expansion through Nanophoton's acquisition, signaling a robust growth trajectory in the biopharmaceutical sector. Lastly, we explore recent market research findings, highlighting the burgeoning potential of the Cancer Biomarkers and Protein Stability Analysis markets, poised for remarkable growth.
Biomarker Discovery
*Neurology
This study investigated the proteome of five brain regions from Parkinson's disease (PD) patients carrying the GBA1 mutation, comparing it to idiopathic PD patients and healthy controls. Utilizing non-targeted, mass spectrometry-based quantitative proteomics, the research unveiled that two proteins were differentially expressed across all examined brain regions, highlighting substantial differences between these areas. This included a pronounced loss of dopaminergic signaling in the substantia nigra and activation of various pathways, such as ceramide synthesis in the cingulate gyrus. Moreover, mitochondrial oxidative phosphorylation was found to be notably inactivated in most brain regions of PD samples, particularly in those with the GBA1 mutation. The findings offer a significant large-scale proteomics dataset, advancing the understanding of PD pathogenesis associated with GBA1 mutations.
*Oncology
This research unveiled that the transcription factor ZNF263 plays a crucial role in enhancing the therapeutic response to EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LUAD), while its loss is associated with resistance. ZNF263 was found significantly reduced in cells and clinical tumors resistant to the EGFR TKI osimertinib, with its overexpression improving initial responses and reducing the emergence of resistant cell populations. The study demonstrated that ZNF263 suppresses EGFR expression through DNA hypermethylation of its promoter and disrupts nuclear EGFR functions, thus combating tumor cell survival and resistance. These findings highlight ZNF263's potential in achieving a durable response to EGFR-targeted therapies, suggesting a promising avenue for overcoming resistance and achieving complete tumor response in LUAD treatments.
*Psychiatry
This study integrated data from brain and blood proteomics with extensive genome-wide association study statistics to identify key proteins linked to suicide attempts (SA). Utilizing a range of methodologies including Mendelian randomization, Bayesian colocalization, and proteome-wide association studies, researchers identified ten proteins in brain proteomics with significant associations to SA. Notably, three of these proteins—GLRX5, GMPPB, and FUCA2—demonstrated strong colocalization evidence and were predominantly expressed in glutamatergic neuronal cells. While the study also identified proteins in blood proteomics, including one significant protein, PEAR1, it found limited colocalization evidence for these. This research offers new insights into the biological mechanisms underlying SA and points towards potential new therapeutic targets.
Proteomics Innovation
*Protein Structure
This study introduced CombFold, an innovative algorithm that leverages AlphaFold2 to predict structures of large protein assemblies. This method combines a combinatorial and hierarchical approach to assemble protein complexes from pairwise interactions, enhancing the prediction accuracy for complex structures. In tests on two datasets comprising 60 large, asymmetric protein assemblies, CombFold achieved over 72% accuracy among its top-10 predictions and demonstrated a 20% improvement in structural coverage compared to existing Protein Data Bank entries. The method also integrates experimental data like crosslinking mass spectrometry for enhanced prediction accuracy, positioning CombFold as a significant advancement for structural biology, particularly in understanding complex protein interactions.
*Protein Homo-Oligomerization
This research has successfully expanded our knowledge of protein homo-oligomerization across various domains of life, utilizing AlphaFold2 to model over 8,000 homomer structures from four proteomes, including archaea, bacteria, and eukaryotes. This comprehensive analysis, which increased structural coverage of homomers by 50%-150% per proteome, identified hundreds of interface types, three of which were experimentally validated. The study uncovered that a significant portion of proteins within these proteomes form homomers, with about 45% in archaeal and bacterial proteomes and 20% in eukaryotic proteomes. These findings not only enhance our understanding of protein complex formation but also provide a foundational dataset for proteome-wide structuromics analyses, offering new insights into disease mutations and the evolution of quaternary structures, particularly highlighting coiled-coil regions as significant contributors to quaternary structure evolution in humans.
*Protein Citrullination
This study has successfully generated a detailed atlas of citrullination sites within the HL60 leukemia cell line, transformed into neutrophil-like cells. Employing quantitative mass spectrometry-based proteomics, researchers identified and quantified 14,056 citrullination sites across 4,008 proteins, highlighting the enzyme PADI4's extensive regulation upon its inhibition. This atlas offers unprecedented insights into the widespread occurrence of citrullination and its implications in rheumatoid arthritis (RA), notably through the distinct reactivity of anti-CCP-positive and anti-CCP-negative synovial fluids from RA patients to specific citrullinated peptides. This research not only expands our understanding of citrullination's regulatory roles across various proteins, including histones and transcription regulators but also underscores its potential clinical relevance in autoimmune diseases like RA.
领英推荐
*Protein Thermo-sensing
This study demonstrated how cells adapt to environmental changes by forming RNA-seeded amyloid bodies (A-bodies), which vary in molecular composition based on the specific stress encountered. This research uncovered that the structural configuration of proteins plays a crucial role in their aggregation into A-bodies in response to heat shock. Through manipulation of structural elements within these proteins, scientists were able to control whether or not specific proteins would aggregate under elevated temperatures. The findings propose a novel model in which the thermal stability of proteins, dictated by temperature-sensitive structural regions, acts as an intrinsic mechanism for post-translational regulation. This mechanism allows for a selective and rapid cellular response to stress, offering a refined understanding of how physiological amyloid aggregation can be controlled.
*Protein Degradation
This study has developed a workflow and software to analyze peptides generated by human 20S proteasomes from entire proteins, applying it to 15 proteins including tau and α-Synuclein. This research confirmed the production of a significant variety of cis-spliced peptides, with trans-spliced ones being less common. Both non-spliced and spliced peptides showed specific characteristics, suggesting a regulated mechanism for peptide hydrolysis and splicing by proteasomes. Importantly, peptides were not randomly distributed within protein sequences but concentrated in specific hotspots, influenced by sequence motifs and proteasomal preferences. At the sequence level, distinct preferences for peptide hydrolysis and splicing hint at a competition between these two activities during protein degradation, challenging the notion that proteasome-catalyzed peptide splicing is a rare event and underscoring its biochemical specificity and regulatory complexity.
Industry Update
*Acquisition
MorphoSys is set to be acquired by Novartis in a $2.9 billion deal, alongside selling the rights to its lymphoma drug tafasitamab to Incyte for $25 million. The transactions will integrate MorphoSys' assets, including a myelofibrosis drug with uncertain approval prospects, into Novartis, while Incyte gains full control over tafasitamab, approved for relapsed lymphoma. This strategic move enhances Novartis' hematology portfolio and presents Incyte with an opportunity to bolster its product offerings despite the competitive market challenges.
*Acquisition
Bruker Corporation enhances its molecular microscopy portfolio by acquiring Nanophoton Corporation, a Japanese innovator in research Raman microscopy, known for its advanced Raman microscopes tailored for academic and industrial research. This strategic acquisition, not disclosing financial terms, strengthens Bruker's offerings in life sciences, biopharma, and materials science, leveraging Nanophoton's expertise in producing high-speed, high-resolution Raman microscopy systems. Nanophoton, with a 2023 revenue of about $5 million and nearly breaking even, joins Bruker to push global growth and innovation in Raman imaging technologies.
*Market Research
The global Cancer Biomarkers Market is poised for significant growth, expected to surge from $14.08 billion in 2022 to $50.47 billion by 2030, at a CAGR of 17.30%. This growth is driven by the rising prevalence of cancer, advancements in biomarker technology, and the increasing focus on personalized medicine. The market's expansion is further supported by advancements in non-invasive diagnostic techniques and the growing application of biomarkers in drug development and patient monitoring.
*Market Research
The Protein Stability Analysis Market is projected to grow from $2.43 billion in 2024 to $5.48 billion by 2031, at a CAGR of 11.35%. This growth is fueled by increasing demand for biopharmaceuticals, advancements in protein stability analysis technologies, and a rising focus on personalized medicine. Significant market drivers include the need for precise analysis in the development and manufacturing of protein-based therapeutic products and the application of advanced analytical techniques and AI in protein stability studies.
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