Visualizations of biomolecular structures empower us to gain insights into biological functions, generate testable hypotheses, and communicate biological concepts. Typical visualizations (such as ball and stick) primarily depict covalent bonds. In contrast, non-covalent contacts between atoms, which govern normal physiology, pathogenesis, and drug action, are seldom visualized. We present the Protein Contacts Atlas, an interactive resource of non-covalent contacts from over 100,000 PDB crystal structures. We developed multiple representations for visualization and analysis of non-covalent contacts at different scales of organization: atoms, residues, secondary structure, subunits, and entire complexes. The Protein Contacts Atlas enables researchers from different disciplines to investigate diverse questions in the framework of non-covalent contacts, including the interpretation of allostery, disease mutations and polymorphisms, by exploring individual subunits, interfaces, and protein–ligand contacts and by mapping external information. The Protein Contacts Atlas is available at http://www.mrc-lmb.cam.ac.uk/pca/ and also through PDBe.
Natural genetic variation in the human genome is a cause of individual differences in responses to medications and is an underappreciated burden on public health. Although 108 G-protein-coupled receptors (GPCRs) are the targets of 475 (∼34%) Food and Drug Administration (FDA)-approved drugs and account for a global sales volume of over 180 billion US dollars annually, the prevalence of genetic variation among GPCRs targeted by drugs is unknown. By analyzing data from 68,496 individuals, we find that GPCRs targeted by drugs show genetic variation within functional regions such as drug- and effector-binding sites in the human population. We experimentally show that certain variants of μ-opioid and Cholecystokinin-A receptors could lead to altered or adverse drug response. By analyzing UK National Health Service drug prescription and sales data, we suggest that characterizing GPCR variants could increase prescription precision, improving patients’ quality of life, and relieve the economic and societal burden due to variable drug responsiveness.
It is increasingly appreciated that alternative splicing
plays a key role in generating functional specificity
and diversity in cancer. However, the mechanisms
by which cancer mutations perturb splicing remain
unknown. Here, we developed a network-based strategy,
DrAS-Net, to investigate more than 2.5 million
variants across cancer types and link somatic mutations
with cancer-specific splicing events. We identi-
fied more than 40,000 driver variant candidates and
their 80,000 putative splicing targets deregulated in
33 cancer types and inferred their functional impact.
Strikingly, tumors with splicing perturbations show
reduced expression of immune system-related
genes and increased expression of cell proliferation
markers. Tumors harboring different mutations in
the same gene often exhibit distinct splicing perturbations.
Further stratification of 10,000 patients based
on their mutation-splicing relationships identifies
subtypes with distinct clinical features, including survival
rates. Our work reveals how single-nucleotide
changes can alter the repertoires of splicing isoforms,
providing insights into oncogenic mechanisms for
The paper by Li et al can be found here.
Welcome to Xiaohan who has started his postdoc in our group last month!
Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases.
Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential
and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of
proteins by mediating protein interactions and facilitating spatial organization in a repeat-dependent manner. During evolution,
homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated
detrimental effects such as unregulated phase separation and protein aggregation. Their presence facilitates rapid protein
divergence through accumulation of amino acid substitutions, which often affect linear motifs and post-translational-modification
sites. These substitutions may result in rewiring protein interaction and signaling networks. Thus, homorepeats are distinct
modules that are often retained in stringently regulated proteins. Their presence facilitates rapid exploration of the genotype–
phenotype landscape of a population, thereby contributing to adaptation and fitness.
The paper by Chavali et al can be found here.
The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.
Intrinsically disordered proteins (IDPs) can protect cells from diverse stresses by forming higher order assemblies such as reversible aggregates or granules. Recently, Boothby et al. show that IDPs protect tardigrades against desiccation by forming a glass-like amorphous matrix, highlighting that material properties of disordered proteins can confer adaptation during stress.
The paper by Chavali et al can be found here.
Nuclear magnetic resonance spectroscopy is transforming our views of proteins by revealing how their structures and dynamics are closely intertwined to underlie their functions and interactions. Compelling representations of proteins as statistical ensembles are uncovering the presence and biological relevance of conformationally heterogeneous states, thus gradually making it possible to go beyond the dichotomy between order and disorder through more quantitative descriptions that span the continuum between them.
The paper by Sormanni et al can be found here.
In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence-structure-function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution.
The review by M. Madan Babu can be found here.
Prof. Arthur M. Lesk from Pennsylvania State University has been visiting our group since last August, he will be here until the end of Summer. Dr Daniela Rhodes from Nanyang Technological University in Singapore visited us last month. Finally, we have Dr Richard Rottger from Denmark who joined our group as a sabbatical visitor last month. He will be with us for a couple of months.