SCOWLP classification: Structural comparison and analysis of protein binding regions

<p>Abstract</p> <p>Background</p> <p>Detailed information about protein interactions is critical for our understanding of the principles governing protein recognition mechanisms. The structures of many proteins have been experimentally determined in complex with different ligands bound either in the same or different binding regions. Thus, the structural interactome requires the development of tools to classify protein binding regions. A proper classification may provide a general view of the regions that a protein uses to bind others and also facilitate a detailed comparative analysis of the interacting information for specific protein binding regions at atomic level. Such classification might be of potential use for deciphering protein interaction networks, understanding protein function, rational engineering and design.</p> <p>Description</p> <p>Protein binding regions (PBRs) might be ideally described as well-defined separated regions that share no interacting residues one another. However, PBRs are often irregular, discontinuous and can share a wide range of interacting residues among them. The criteria to define an individual binding region can be often arbitrary and may differ from other binding regions within a protein family. Therefore, the rational behind protein interface classification should aim to fulfil the requirements of the analysis to be performed.</p> <p>We extract detailed interaction information of protein domains, peptides and interfacial solvent from the SCOWLP database and we classify the PBRs of each domain family. For this purpose, we define a similarity index based on the overlapping of interacting residues mapped in pair-wise structural alignments. We perform our classification with agglomerative hierarchical clustering using the complete-linkage method. Our classification is calculated at different similarity cut-offs to allow flexibility in the analysis of PBRs, feature especially interesting for those protein families with conflictive binding regions.</p> <p>The hierarchical classification of PBRs is implemented into the SCOWLP database and extends the SCOP classification with three additional family sub-levels: Binding Region, Interface and Contacting Domains. SCOWLP contains 9,334 binding regions distributed within 2,561 families. In 65% of the cases we observe families containing more than one binding region. Besides, 22% of the regions are forming complex with more than one different protein family.</p> <p>Conclusion</p> <p>The current SCOWLP classification and its web application represent a framework for the study of protein interfaces and comparative analysis of protein family binding regions. This comparison can be performed at atomic level and allows the user to study interactome conservation and variability. The new SCOWLP classification may be of great utility for reconstruction of protein complexes, understanding protein networks and ligand design. SCOWLP will be updated with every SCOP release. The web application is available at <url>http://www.scowlp.org</url>.</p

The scattering and extinction properties of nanodiamonds

The study of scattering and extinction properties of possible nanodiamond grains in the ISM are reported. Calculations using Discrete Dipole Approximation (DDA) for varying ellipsoidal shapes and sizes from 2.5 to $10 nm$ are considered. Nanodiamonds show negligible extinction from IR to near-UV and very sharp far-UV rise. Comparison with observations rule out possibility of independent nanodiamond dust but point towards possibility of nanodiamonds as a component in the ISM. Radiation induced transformations may lead to carbonaceous grains with different core and mantles. So calculations are also performed for a core-mantle target model with nanodiamond core in graphite mantles. The graphite extinction features get modified with the peak at 2175 \AA{} being lowered, broadened, blue shifted and accompanied by enhanced extinction in the far-UV. Such variations in the 2175 \AA{} band and simultaneous far-UV rise are observed along some sources. A three component dust model incorporating silicate, graphite and graphite with nanodiamond core is also considered. The model extinction compares very well with the average galactic extinction in the complete range from 0.2 to $10 \mu m^{-1}$. The best fit requires small size and small number of nanodiamonds.Comment: Accepted for publication in MNRAS; 8 Figure

P-selectin mobility undergoes a sol-gel transition as it diffuses from exocytosis sites into the cell membrane

In response to vascular damage, P-selectin molecules are secreted onto the surface of cells that line our blood vessels. They then serve as mechanical anchors to capture leucocytes from the blood stream. Here, we track individual P-selectin molecules released at the surface of live endothelial cells following stimulated secretion. We find P-selectin initially shows fast, unrestricted diffusion but within a few minutes, movement becomes increasingly restricted and ~50% of the molecules become completely immobile; a process similar to a sol-gel transition. We find removal of the extracellular C-type lectin domain (ΔCTLD) and/or intracellular cytoplasmic tail domain (ΔCT) has additive effects on diffusive motion while disruption of the adapter complex, AP2, or removal of cell-surface heparan sulphate restores mobility of full-length P-selectin close to that of ΔCT and ΔCTLD respectively. We have found P-selectin spreads rapidly from sites of exocytosis and evenly decorates the cell surface, but then becomes less mobile and better-suited to its mechanical anchoring function

Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes.

PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype-genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes

Misperceptions in the Trajectories of Objects undergoing Curvilinear Motion

Trajectory perception is crucial in scene understanding and action. A variety of trajectory misperceptions have been reported in the literature. In this study, we quantify earlier observations that reported distortions in the perceived shape of bilinear trajectories and in the perceived positions of their deviation. Our results show that bilinear trajectories with deviation angles smaller than 90 deg are perceived smoothed while those with deviation angles larger than 90 degrees are perceived sharpened. The sharpening effect is weaker in magnitude than the smoothing effect. We also found a correlation between the distortion of perceived trajectories and the perceived shift of their deviation point. Finally, using a dual-task paradigm, we found that reducing attentional resources allocated to the moving target causes an increase in the perceived shift of the deviation point of the trajectory. We interpret these results in the context of interactions between motion and position systems

Homogeneously derived transit timings for 17 exoplanets and reassessed TTV trends for WASP-12 and WASP-4

We homogeneously analyse ∼3.2 × 105 photometric measurements for ∼1100 transit lightcurves belonging to 17 exoplanet hosts. The photometric data cover 16 years 2004–2019 and include amateur and professional observations. Old archival lightcurves were reprocessed using up-to-date exoplanetary parameters and empirically debiased limb-darkening models. We also derive self-consistent transit and radial-velocity fits for 13 targets. We confirm the nonlinear TTV trend in the WASP-12 data at a high significance, and with a consistent magnitude. However, Doppler data reveal hints of a radial acceleration about ( − 7.5 ± 2.2) m/s/yr, indicating the presence of unseen distant companions, and suggesting that roughly 10 per cent of the observed TTV was induced via the light-travel (or Roemer) effect. For WASP-4, a similar TTV trend suspected after the recent TESS observations appears controversial and model-dependent. It is not supported by our homogeneus TTV sample, including 10 ground-based EXPANSION lightcurves obtained in 2018 simultaneously with TESS. Even if the TTV trend itself does exist in WASP-4, its magnitude and tidal nature are uncertain. Doppler data cannot entirely rule out the Roemer effect induced by possible distant companions

Beauty Is in the Eye of the Beholder: Proteins Can Recognize Binding Sites of Homologous Proteins in More than One Way

Understanding the mechanisms of protein–protein interaction is a fundamental problem with many practical applications. The fact that different proteins can bind similar partners suggests that convergently evolved binding interfaces are reused in different complexes. A set of protein complexes composed of non-homologous domains interacting with homologous partners at equivalent binding sites was collected in 2006, offering an opportunity to investigate this point. We considered 433 pairs of protein–protein complexes from the ABAC database (AB and AC binary protein complexes sharing a homologous partner A) and analyzed the extent of physico-chemical similarity at the atomic and residue level at the protein–protein interface. Homologous partners of the complexes were superimposed using Multiprot, and similar atoms at the interface were quantified using a five class grouping scheme and a distance cut-off. We found that the number of interfacial atoms with similar properties is systematically lower in the non-homologous proteins than in the homologous ones. We assessed the significance of the similarity by bootstrapping the atomic properties at the interfaces. We found that the similarity of binding sites is very significant between homologous proteins, as expected, but generally insignificant between the non-homologous proteins that bind to homologous partners. Furthermore, evolutionarily conserved residues are not colocalized within the binding sites of non-homologous proteins. We could only identify a limited number of cases of structural mimicry at the interface, suggesting that this property is less generic than previously thought. Our results support the hypothesis that different proteins can interact with similar partners using alternate strategies, but do not support convergent evolution

Janus-faced EPHB4-associated disorders: novel pathogenic variants and unreported intrafamilial overlapping phenotypes.

PURPOSE: Several clinical phenotypes including fetal hydrops, central conducting lymphatic anomaly or capillary malformations with arteriovenous malformations 2 (CM-AVM2) have been associated with EPHB4 (Ephrin type B receptor 4) variants, demanding new approaches for deciphering pathogenesis of novel variants of uncertain significance (VUS) identified in EPHB4, and for the identification of differentiated disease mechanisms at the molecular level. METHODS: Ten index cases with various phenotypes, either fetal hydrops, CM-AVM2, or peripheral lower limb lymphedema, whose distinct clinical phenotypes are described in detail in this study, presented with a variant in EPHB4. In vitro functional studies were performed to confirm pathogenicity. RESULTS: Pathogenicity was demonstrated for six of the seven novel EPHB4 VUS investigated. A heterogeneity of molecular disease mechanisms was identified, from loss of protein production or aberrant subcellular localization to total reduction of the phosphorylation capability of the receptor. There was some phenotype-genotype correlation; however, previously unreported intrafamilial overlapping phenotypes such as lymphatic-related fetal hydrops (LRFH) and CM-AVM2 in the same family were observed. CONCLUSION: This study highlights the usefulness of protein expression and subcellular localization studies to predict EPHB4 variant pathogenesis. Our accurate clinical phenotyping expands our interpretation of the Janus-faced spectrum of EPHB4-related disorders, introducing the discovery of cases with overlapping phenotypes