Protein energy landscapes are highly complex, yet the vast majority of states within them tend to be invisible to experimentalists. Here, using site-directed mutagenesis and exploiting the simplicity of tandem-repeat protein structures, we delineate a network of these states and the routes between them. We show that our target, gankyrin, a 226-residue 7-ankyrin-repeat protein, can access two alternative (un)folding pathways. We resolve intermediates as well as transition states, constituting a comprehensive series of snapshots that map early and late stages of the two pathways and show both to be polarized such that the repeat array progressively unravels from one end of the molecule or the other. Strikingly, we find that the protein folds via one pathway but unfolds via a different one. The origins of this behavior can be rationalized using the numerical results of a simple statistical mechanics model that allows us to visualize the equilibrium behavior as well as single-molecule folding/unfolding trajectories, thereby filling in the gaps that are not accessible to direct experimental observation. Our study highlights the complexity of repeat-protein folding arising from their symmetrical structures; at the same time, however, this structural simplicity enables us to dissect the complexity and thereby map the precise topography of the energy landscape in full breadth and remarkable detail. That we can recapitulate the key features of the folding mechanism by computational analysis of the native structure alone will help toward the ultimate goal of designed amino-acid sequences with made-to-measure folding mechanisms-the Holy Grail of protein folding.
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http://dx.doi.org/10.1021/jacs.5b07370 | DOI Listing |
Sci Rep
December 2024
Department of Psychiatry and Behavioral Sciences and Weill Center for Neurosciences, University of California, San Francisco, CA, 94107, USA.
Telomere attrition is a hallmark of biological aging, contributing to cellular replicative senescence. However, few studies have examined the determinants of telomere attrition in vivo in humans. Mitochondrial Health Index (MHI), a composite marker integrating mitochondrial energy-transformation capacity and content, may be one important mediator of telomere attrition, as it could impact telomerase activity, a direct regulator of telomere maintenance.
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December 2024
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
The Epstein-Barr virus (EBV) is widespread and has been related to a variety of malignancies as well as infectious mononucleosis. Despite the lack of a vaccination, antiviral medications offer some therapy alternatives. The EBV BZLF1 gene significantly impacts viral replication and infection severity.
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December 2024
Bioinformatics Laboratory, College of Computing, University Mohammed VI Polytechnic, Ben Guerir, Morocco.
Hepatitis C virus (HCV) presents a significant global health issue due to its widespread prevalence and the absence of a reliable vaccine for prevention. While significant progress has been achieved in therapeutic interventions since the disease was first identified, its resurgence underscores the need for innovative strategies to combat it. The nonstructural protein NS5A is crucial in the life cycle of the HCV, serving as a significant factor in both viral replication and assembly processes.
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December 2024
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Bologna, Italy.
Acute myeloid leukemia (AML) is an aggressive disease with a high relapse rate. In this study, we map the metabolic profile of CD34(CD38) AML cells and the extracellular vesicle signatures in circulation from AML patients at diagnosis. CD34 AML cells display high antioxidant glutathione levels and enhanced mitochondrial functionality, both associated with poor clinical outcomes.
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December 2024
University of Jammu, Jammu and Kashmir, 180006, India.
Nesfatin-1 is a crucial regulator of energy homeostasis in mammals and fishes, however, its metabolic role remains completely unexplored in amphibians, reptiles, and birds. Therefore, present study elucidates role of nesfatin-1 in glucose homeostasis in wall lizard wherein fasting stimulated hepatic nucb2/nesfatin-1, glycogen phosphorylase (glyp), phosphoenolpyruvate carboxykinase (pepck), and fructose 1,6-bisphosphatase (fbp), while feeding upregulated pancreatic nucb2/nesfatin-1 and insulin, suggesting towards tissue-specific dual role of nesfatin-1 in glucoregulation. The glycogenolytic/gluconeogenic role of nesfatin-1 was further confirmed by an increase in media glucose levels along with heightened hepatic pepck and fbp expression and concomitant decline in liver glycogen content in nesfatin-1-treated liver of wall lizard.
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