A network analysis of crab metamorphosis and the hypothesis of development as a process of unfolding of an intensive complexity.
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ABSTRACT:
SUBMITTER: Ostachuk A
PROVIDER: S-EPMC8100167 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Since the proposal of Anfinsen's thermodynamic hypothesis in 1963, our understanding of protein folding and dynamics has gained significant appreciation of its nuance and complexity. Intrinsically disordered proteins, chameleonic sequences, morpheeins, and metamorphic proteins have broadened the protein folding paradigm. Here, we discuss noncanonical protein folding patterns, with an emphasis on metamorphic proteins, and we review known metamorphic proteins that occur naturally and that have been engineered in the laboratory. Finally, we discuss research areas surrounding metamorphic proteins that are primed for future exploration, including evolution, drug discovery, and the quest for previously unrecognized metamorphs. As we enter an age where we are capable of complex bioinformatic searches and de novo protein design, we are primed to search for previously unrecognized metamorphic proteins and to design our own metamorphs to act as targeted, switchable drugs; biosensors; and more.
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Project description:Recently we showed that the three-dimensional structure of proteins can be investigated from a network perspective, where the amino acid residues represent the nodes in the network and the noncovalent interactions between them are considered for the edge formation. In this study, the dynamical behavior of such networks is examined by considering the example of T4 lysozyme. The equilibrium dynamics and the process of unfolding are followed by simulating the protein at 300 K and at higher temperatures (400 K and 500 K), respectively. The snapshots of the protein structure from the simulations are represented as protein structure networks in which the strength of the noncovalent interactions is considered an important criterion in the construction of edges. The profiles of the network parameters, such as the degree distribution and the size of the largest cluster (giant component), were examined as a function of interaction strength at different temperatures. Similar profiles are seen at all the temperatures. However, the critical strength of interaction (Icritical) and the size of the largest cluster at all interaction strengths shift to lower values at 500 K. Further, the folding/unfolding transition is correlated with contacts evaluated at Icritical and with the composition of the top large clusters obtained at interaction strengths greater than Icritical. Finally, the results are compared with experiments, and predictions are made about the residues, which are important for stability and folding. To summarize, the network analysis presented in this work provides insights into the details of the changes occurring in the protein tertiary structure at the level of amino acid side-chain interactions, in both the equilibrium and the unfolding simulations. The method can also be employed as a valuable tool in the analysis of molecular dynamics simulation data, since it captures the details at a global level, which may elude conventional pairwise interaction analysis.
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Project description:A hypothesis is proposed on a potential role of protein dielectricity as an unfolding factor in protein-protein interactions. It is suggested that large protein complexes and aggregation seeds can unfold target proteins by virtue of their effect on the dielectric properties of water at the protein-solvent interface. Here, similar to the effect of membrane surfaces, protein surface can cause decrease in the local dielectric constant of solvent and thereby induce structural changes in a target protein approaching this surface. Some potential implementations of this hypothetical mechanism are also discussed.
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Project description:Ovarian development is a key physiological process that holds great significance in the reproduction of the Chinese mitten crab (Eriocheir sinensis), which is an economically important crab species for aquaculture. However, there is limited knowledge for the regulatory mechanisms of ovarian development. To study the molecular mechanisms of its ovarian development, transcriptome analysis was performed in the ovary and hepatopancreas of E. sinensis during ovarian stages I (oogonium proliferation), II (endogenous vitellogenesis), and III (exogenous vitellogenesis). The results showed that 5,520 and 226 genes were differentially expressed in the ovary and hepatopancreas, respectively. For KEGG enrichment analysis, the differentially expressed genes in the ovary were significantly clustered in phototransduction-fly, phagosome, and ECM-receptor interaction. Significantly enriched pathways in the hepatopancreas included fatty acid biosynthesis, fatty acid metabolism, and riboflavin metabolism. Further analysis showed that 25 genes and several pathways were mainly involved in oogenesis, including the ubiquitin-proteasome pathway, cyclic AMP-protein kinase A signaling pathway, and mitogen-activated protein kinase signaling pathway. Twenty-five candidate genes involved in vitellogenesis and endocrine regulation were identified, such as vitellogenin, vitellogenin receptor, estrogen sulfotransferase, ecdysone receptor, prostaglandin reductase 1, hematopoietic prostaglandin D synthase and juvenile hormone acid O-methyltransferase. Fifty-six genes related to nutritional metabolism were identified, such as fatty acid synthase, long-chain-fatty-acid-CoA ligase 4, 1-acyl-sn-glycerol-3-phosphate acyltransferase 4, fatty acid-binding protein, and glycerol-3-phosphate acyltransferase 1. These results highlight the genes involved in ovarian development and nutrition deposition, which enhance our understanding of the regulatory pathways and physiological processes of crustacean ovarian development.
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Project description:High pressure (HP) or urea is commonly used to disturb folding species. Pressure favors the reversible unfolding of proteins by causing changes in the volumetric properties of the protein-solvent system. However, no mechanistic model has fully elucidated the effects of urea on structure unfolding, even though protein-urea interactions are considered to be crucial. Here, we provide NMR spectroscopy and 3D reconstructions from X-ray scattering to develop the "push-and-pull" hypothesis, which helps to explain the initial mechanism of chemical unfolding in light of the physical events triggered by HP. In studying MpNep2 from Moniliophthora perniciosa, we tracked two cooperative units using HP-NMR as MpNep2 moved uphill in the energy landscape; this process contrasts with the overall structural unfolding that occurs upon reaching a threshold concentration of urea. At subdenaturing concentrations of urea, we were able to trap a state in which urea is preferentially bound to the protein (as determined by NMR intensities and chemical shifts); this state is still folded and not additionally exposed to solvent [fluorescence and small-angle X-ray scattering (SAXS)]. This state has a higher susceptibility to pressure denaturation (lower p1/2 and larger ?Vu); thus, urea and HP share concomitant effects of urea binding and pulling and water-inducing pushing, respectively. These observations explain the differences between the molecular mechanisms that control the physical and chemical unfolding of proteins, thus opening up new possibilities for the study of protein folding and providing an interpretation of the nature of cooperativity in the folding and unfolding processes.
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Project description:Purpose Aphasia is a complex, neurogenic language disorder, with different aphasia syndromes hallmarked by impairment in fluency, auditory comprehension, naming, and/or repetition. Broad, standardized assessments of language domains and specific language and cognitive assessments provide a holistic impairment profile of a person with aphasia. While many recognize the correlations between assessments, there remains a need to continue understanding the complexity of relationships between assessments for the purpose of better characterization of language impairment profiles of persons with aphasia. We explored the use of network analysis to identify the complex relationships between a variety of language assessments. Method We computed a regularized partial correlation network and a directed acyclic graph network to estimate the relations between different aphasia assessments in 128 persons with aphasia. Results Western Aphasia Battery-Revised Comprehension subtest was the most central assessment in the aphasia symptom network, whereas the Philadelphia Naming Test had the most putative causal influence on other assessments. Additionally, the language assessments segregated into three empirically derived communities denoting phonology, semantics, and syntax. Furthermore, several assessments, including the Philadelphia Naming Test, belonged to multiple communities, suggesting that certain assessments may capture multiple language impairments. Conclusion We discuss the implications of using a network analysis approach for clinical intervention and driving forward novel questions in the field of clinical aphasiology. Supplemental Material https://doi.org/10.23641/asha.16620229.
| S-EPMC9132069 | biostudies-literature
Project description:Spiders have evolved a unique male copulatory organ, the pedipalp bulb. The morphology of the bulb is species specific and plays an important role in species recognition and prezygotic reproductive isolation. Despite its importance for spider biodiversity, the mechanisms that control bulb development are virtually unknown. We have used confocal laser scanning microscopy (CLSM) and diffusible iodine-based contrast-enhanced micro computed tomography (dice-µCT) to study bulb development in the spider Parasteatoda tepidariorum. These imaging technologies enabled us to study bulb development in situ, without the use of destructive procedures for the first time. We show here that the inflated pedipalp tip in the subadult stage is filled with haemolymph that rapidly coagulates. Coagulation indicates histolytic processes that disintegrate tibia and tarsus, similar to histolytic processes during metamorphosis in holometabolous insects. The coagulated material contains cell inclusions that likely represent the cell source for the re-establishment of tarsus and tibia after histolysis, comparable to the histoblasts in insect metamorphosis. The shape of the coagulated mass prefigures the shape of the adult tarsus (cymbium) like a blueprint for the histoblasts. This suggests a unique role for controlled coagulation after histolysis in the metamorphosis-like morphogenesis of the male pedipalp.
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Project description:BackgroundThe study objective was to analyse the implementation challenges experienced in carrying out the IMPROVE programme. This programme was designed to implement checklist-related improvement initiatives based on the national perioperative guidelines using a stepped-wedge trial design. A process analysis was carried out to investigate the involvement in the implementation activities.MethodsAn involvement rating measure was developed to express the extent to which the implementation programme was carried out in the hospitals. This measure reflects the number of IMPROVE-implementation activities executed and the estimated participation in these activities in all nine participating hospitals. These data were compared with prospectively collected field notes.ResultsConsiderable variation between the hospitals was found with involvement ratings ranging from 0 to 6 (mean per measurement = 1.83 on a scale of 0-11). Major implementation challenges were respectively the study design (fixed design, time planning, long duration, repeated measurements, and data availability); the selection process of hospitals, departments and key contact person(s) (inadequately covering the entire perioperative team and stand-alone surgeons); the implementation programme (programme size and scope, tailoring, multicentre, lack of mandate, co-interventions by the Inspectorate, local intervention initiatives, intervention fatigue); and competitive events such as hospital mergers or the introduction of new IT systems, all reducing involvement.ConclusionsThe process analysis approach helped to explain the limited and delayed execution of the IMPROVE-implementation programme. This turned out to be very heterogeneous between hospitals, with variation in the number and content of implementation activities carried out. The identified implementation challenges reflect a high complexity with regard to the implementation programme, study design and setting. The involvement of the target professionals was put under pressure by many factors. We mostly encountered challenges, but at the same time we provide solutions for addressing them. A less complex implementation programme, a less fixed study design, a better thought-out selection of contact persons, as well as more commitment of the hospital management and surgeons would likely have contributed to better implementation results.Trial registrationDutch Trial Registry: NTR3568 , retrospectively registered on 2 August 2012.
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Project description:BackgroundThe architectural organization of protein structures has been the focus of intense research since it can hopefully lead to an understanding of how proteins fold. In earlier works we had attempted to identify the inherent structural organization in proteins through a study of protein topology. We obtained a modular partitioning of protein structures with the modules correlating well with experimental evidence of early folding units or "foldons". Residues that connect different modules were shown to be those that were protected during the transition phase of folding.Methodology/principal findingsIn this work, we follow the topological path of ubiquitin through molecular dynamics unfolding simulations. We observed that the use of recurrence quantification analysis (RQA) could lead to the identification of the transition state during unfolding. Additionally, our earlier contention that the modules uncovered through our graph partitioning approach correlated well with early folding units was vindicated through our simulations. Moreover, residues identified from native structure as connector hubs and which had been shown to be those that were protected during the transition phase of folding were indeed more stable (less flexible) well beyond the transition state. Further analysis of the topological pathway suggests that the all pairs shortest path in a protein is minimized during folding.ConclusionsWe observed that treating a protein native structure as a network by having amino acid residues as nodes and the non-covalent interactions among them as links allows for the rationalization of many aspects of the folding process. The possibility to derive this information directly from 3D structure opens the way to the prediction of important residues in proteins, while the confirmation of the minimization of APSP for folding allows for the establishment of a potentially useful proxy for kinetic optimality in the validation of sequence-structure predictions.
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Project description:Guanine quadruplexes (GQs) are non-canonical nucleic acid structures involved in many biological processes. GQs formed in single-stranded regions often need to be unwound by cellular machinery, so their mechanochemical properties are important. Here, we performed steered molecular dynamics simulations of human telomeric GQs to study their unfolding. We examined four pulling regimes, including a very slow setup with pulling velocity and force load accessible to high-speed atomic force microscopy. We identified multiple factors affecting the unfolding mechanism, i.e.,: (i) the more the direction of force was perpendicular to the GQ channel axis (determined by GQ topology), the more the base unzipping mechanism happened, (ii) the more parallel the direction of force was, GQ opening and cross-like GQs were more likely to occur, (iii) strand slippage mechanism was possible for GQs with an all-anti pattern in a strand, and (iv) slower pulling velocity led to richer structural dynamics with sampling of more intermediates and partial refolding events. We also identified that a GQ may eventually unfold after a force drop under forces smaller than those that the GQ withstood before the drop. Finally, we found out that different unfolding intermediates could have very similar chain end-to-end distances, which reveals some limitations of structural interpretations of single-molecule spectroscopic data.
| S-EPMC10428220 | biostudies-literature