Residue-residue coevolution has been observed across a number of protein-protein interfaces, but the extent of residue coevolution between protein families on the whole-proteome scale has not been ...systematically studied. We investigate coevolution between 5.4 million pairs of proteins in
and between 3.9 millions pairs in
We find strong coevolution for binary complexes involved in metabolism and weaker coevolution for larger complexes playing roles in genetic information processing. We take advantage of this coevolution, in combination with structure modeling, to predict protein-protein interactions (PPIs) with an accuracy that benchmark studies suggest is considerably higher than that of proteome-wide two-hybrid and mass spectrometry screens. We identify hundreds of previously uncharacterized PPIs in
and
that both add components to known protein complexes and networks and establish the existence of new ones.
Abstract
Eukaryotic proteins often feature modular domain structures comprising globular domains that are connected by linker regions and intrinsically disordered regions that may contain important ...functional motifs. The intramolecular interactions of globular domains and nonglobular regions can play critical roles in different aspects of protein function. However, studying these interactions and their regulatory roles can be challenging due to the flexibility of nonglobular regions, the long insertions separating interacting modules, and the transient nature of some interactions. Obtaining the experimental structures of multiple domains and functional regions is more difficult than determining the structures of individual globular domains. High‐quality structural models generated by AlphaFold offer a unique opportunity to study intramolecular interactions in eukaryotic proteins. In this study, we systematically explored intramolecular interactions between human protein kinase domains (KDs) and potential regulatory regions, including globular domains, N‐ and C‐terminal tails, long insertions, and distal nonglobular regions. Our analysis identified intramolecular interactions between human KDs and 35 different types of globular domains, exhibiting a variety of interaction modes that could contribute to orthosteric or allosteric regulation of kinase activity. We also identified prevalent interactions between human KDs and their flanking regions (N‐ and C‐terminal tails). These interactions exhibit group‐specific characteristics and can vary within each specific kinase group. Although long‐range interactions between KDs and nonglobular regions are relatively rare, structural details of these interactions offer new insights into the regulation mechanisms of several kinases, such as HASPIN, MAPK7, MAPK15, and SIK1B.
ATP‐binding cassette (ABC) systems, characterized by ABC‐type nucleotide‐binding domains (NBDs), play crucial roles in various aspects of human physiology. Human ABCG5 and ABCG8 form a heterodimeric ...transporter that functions in the efflux of sterols. We used sequence similarity search, multiple sequence alignment, phylogenetic analysis, and structure comparison to study the evolutionary origin and sequence signatures of ABCG5 and ABCG8. Orthologs of ABCG5 and ABCG8, supported by phylogenetic analysis and signature residues, were identified in bilaterian animals, Filasterea, Fungi, and Amoebozoa. Such a phylogenetic distribution suggests that ABCG5 and ABCG8 could have originated in the last common ancestor of Amorphea (the unikonts), the eukaryotic group including Amoebozoa and Opisthokonta. ABCG5 and ABCG8 were missing in genomes of various lineages such as snakes, jawless vertebrates, non‐vertebrate chordates, echinoderms, and basal metazoan groups. Amino‐acid changes in key positions in ABCG8 Walker A motif and/or ABCG5 C‐loop were observed in most tetrapod organisms, likely resulted in the loss of ATPase activity at one nucleotide‐binding site. ABCG5 and ABCG8 in Ecdysozoa (such as insects) exhibit elevated evolutionary rates and accumulate various changes in their NBD functional motifs. Alignment inspection revealed several residue positions that show different amino‐acid usages in ABCG5/ABCG8 compared to other ABCG subfamily proteins. These residues were mapped to the structural cores of transmembrane domains (TMDs), the NBD‐TMD interface, and the interface between TMDs. They serve as sequence signatures to differentiate ABCG5/ABCG8 from other ABCG subfamily proteins, and some of them may contribute to substrate specificity of the ABCG5/ABCG8 transporter.
Protein–protein interactions (PPIs) are pivotal for driving diverse biological processes, and any disturbance in these interactions can lead to disease. Thus, the study of PPIs has been a central ...focus in biology. Recent developments in deep learning methods, coupled with the vast genomic sequence data, have significantly boosted the accuracy of predicting protein structures and modeling protein complexes, approaching levels comparable to experimental techniques. Herein, we review the latest advances in the computational methods for modeling 3D protein complexes and the prediction of protein interaction partners, emphasizing the application of deep learning methods deriving from coevolution analysis. The review also highlights biomedical applications of PPI prediction and outlines challenges in the field.
The imitation of mussels and oysters to create high‐performance adhesives is a cutting‐edge field. The introduction of inorganic fillers is shown to significantly alter the adhesive's properties, yet ...the potential of mesoporous materials as fillers in adhesives is overlooked. In this study, the first report on the utilization of mesoporous materials in a biomimetic adhesive system is presented. Incorporating mesoporous silica nanoparticles (MSN) profoundly enhances the adhesion of pyrogallol (PG)–polyethylene imine (PEI) adhesive. As the MSN concentration increases, the adhesion strength to glass substrates undergoes an impressive fivefold improvement, reaching an outstanding 2.5 mPa. The adhesive forms an exceptionally strong bond, to the extent that the glass substrate fractures before joint failure. The comprehensive tests involving various polyphenols, polymers, and fillers reveal an intriguing phenomenon—the molecular structure of polyphenols significantly influences adhesive strength. Steric hindrance emerges as a crucial factor, regulating the balance between π‐cation and charge interactions, which significantly impacts the multicomponent assembly of polyphenol‐PEI‐MSN and, consequently, adhesive strength. This groundbreaking research opens new avenues for the development of novel biomimetic materials.
In this study, the first report on the utilization of mesoporous materials in a biomimetic adhesive system is presented. Incorporating mesoporous silica nanoparticles profoundly enhances the adhesion of pyrogallol–polyethylene imine adhesive. The adhesive forms an exceptionally strong bond, to the extent that the glass substrate fractures before joint failure.
Mechanical forces are fundamental regulators of cell behaviors. However, molecular regulation of mechanotransduction remain poorly understood. Here, we identified the mechanosensitive channels Piezo1 ...and Piezo2 as key force sensors required for bone development and osteoblast differentiation. Loss of Piezo1, or more severely Piezo1/2, in mesenchymal or osteoblast progenitor cells, led to multiple spontaneous bone fractures in newborn mice due to inhibition of osteoblast differentiation and increased bone resorption. In addition, loss of Piezo1/2 rendered resistant to further bone loss caused by unloading in both bone development and homeostasis. Mechanistically, Piezo1/2 relayed fluid shear stress and extracellular matrix stiffness signals to activate Ca
influx to stimulate Calcineurin, which promotes concerted activation of NFATc1, YAP1 and ß-catenin transcription factors by inducing their dephosphorylation as well as NFAT/YAP1/ß-catenin complex formation. Yap1 and ß-catenin activities were reduced in the Piezo1 and Piezo1/2 mutant bones and such defects were partially rescued by enhanced ß-catenin activities.
During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other ...antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.
Protein–protein interactions (PPIs) are involved in almost all essential cellular processes. Perturbation of PPI networks plays critical roles in tumorigenesis, cancer progression, and metastasis. ...While numerous high‐throughput experiments have produced a vast amount of data for PPIs, these data sets suffer from high false positive rates and exhibit a high degree of discrepancy. Coevolution of amino acid positions between protein pairs has proven to be useful in identifying interacting proteins and providing structural details of the interaction interfaces with the help of deep learning methods like AlphaFold (AF). In this study, we applied AF to investigate the cancer protein–protein interactome. We predicted 1,798 PPIs for cancer driver proteins involved in diverse cellular processes such as transcription regulation, signal transduction, DNA repair, and cell cycle. We modeled the spatial structures for the predicted binary protein complexes, 1,087 of which lacked previous 3D structure information. Our predictions offer novel structural insight into many cancer‐related processes such as the MAP kinase cascade and Fanconi anemia pathway. We further investigated the cancer mutation landscape by mapping somatic missense mutations (SMMs) in cancer to the predicted PPI interfaces and performing enrichment and depletion analyses. Interfaces enriched or depleted with SMMs exhibit different preferences for functional categories. Interfaces enriched in mutations tend to function in pathways that are deregulated in cancers and they may help explain the molecular mechanisms of cancers in patients; interfaces lacking mutations appear to be essential for the survival of cancer cells and thus may be future targets for PPI modulating drugs.
Adhesion is the basic ability of many kinds of animals in nature, which ensures the survival and reproduction of animal populations. The aquatic abalone has a strong adhesion capacity. In this study, ...we observed the microscopic morphology of abalone abdominal foot surface, and found that the surface was covered with a large number of fibers. Then five types of force measuring plates were designed and processed for the adhesion test of abalone abdominal foot. According to the test results, the composition of abalone abdominal foot adhesion force was analyzed and the proportion of various adhesion force to the total adhesion force of abalone abdominal foot was calculated. Among them, the vacuum adhesion force accounts for more than half of the total adhesion force of abalone abdominal foot, and its proportion is more than 60%. Van der Waals force also plays an important role, and its proportion is more than 20%. The proportion of capillary force is very small, which is only about 1%. Its main role is to form a liquid film to prevent the gas from flowing into the sucker. The vacuum adhesion of abalone abdominal foot can be further divided into the whole adhesion of abdominal foot, the local adhesion of abdominal foot and the frictional equivalent vacuum adhesion. And the whole adhesion of abdominal foot is basically equivalent to the local adhesion of abdominal foot. This study quantifies the proportion of various adhesion forces to the total adhesion force of the abdominal foot, which provides a reference for the further study of other adhesive creatures and the design of bionic underwater adhesion devices.
The effects of tensile and compressive deformation introduced by the bending deformation on metastable pitting corrosion of 2205 duplex stainless steel were studied by microstructure characterization ...and electrochemical tests. The results demonstrated that both tensile and compressive deformation resulted in severer plastic strains in ferrite than that in austenite, caused the inclusions debonding from matrix and the surrounding micro-cracks. The decrease in critical pitting temperature and pitting potential provides the degradation evidence of the deformed steel. Compared with the as-received samples, bending deformation promoted the initiation frequency and growth rate of metastable pits. It also revealed that higher metastable pitting initiation rate and pit growth under compressive deformation than tensile deformation. The preferential initiation sites and transients’ behavior of metastable pitting were discussed herein.
•Both tensile and compressive deformation degraded pitting resistance of 2205 DSS.•The initiation and growth of metastable pits were enhanced by bending deformation.•Sudden rise and slow decay of transients were observed in the deformed conditions.•The pit initiation sites were transferred from the austenite to the ferrite phase.
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