Prediction of Intrinsic Disorder in MERS-CoV/HCoV-EMC Supports a High Oral-Fecal Transmission

A novel coronavirus, MERS-CoV (NCoV, HCoV-EMC/2012), originating from the Middle-East, has been discovered. Incoming data reveal that the virus is highly virulent to humans. A model that categorizes coronaviuses according to the hardness of their shells was developed before the discovery of MERS-CoV. Using protein intrinsic disorder prediction, coronaviruses were categorized into three groups that can be linked to the levels of oral-fecal and respiratory transmission regardless of genetic proximity. Using this model, MERS-CoV is placed into disorder group C, which consists of coronaviruses that have relatively hard inner and outer shells. The members of this group are likely to persist in the environment for a longer period of time and possess the highest oral-fecal components but relatively low respiratory transmission components. Oral-urine and saliva transmission are also highly possible since both require harder protective shells. Results show that disorder prediction can be used as a tool that suggests clues to look for in further epidemiological investigations

Understanding Viral Transmission Behavior via Protein Intrinsic Disorder Prediction: Coronaviruses

Besides being a common threat to farm animals and poultry, coronavirus (CoV) was responsible for the human severe acute respiratory syndrome (SARS) epidemic in 2002-4. However, many aspects of CoV behavior, including modes of its transmission, are yet to be fully understood. We show that the amount and the peculiarities of distribution of the protein intrinsic disorder in the viral shell can be used for the efficient analysis of the behavior and transmission modes of CoV. The proposed model allows categorization of the various CoVs by the peculiarities of disorder distribution in their membrane (M) and nucleocapsid (N). This categorization enables quick identification of viruses with similar behaviors in transmission, regardless of genetic proximity. Based on this analysis, an empirical model for predicting the viral transmission behavior is developed. This model is able to explain some behavioral aspects of important coronaviruses that previously were not fully understood. The new predictor can be a useful tool for better epidemiological, clinical, and structural understanding of behavior of both newly emerging viruses and viruses that have been known for a long time. A potentially new vaccine strategy could involve searches for viral strains that are characterized by the evolutionary misfit between the peculiarities of the disorder distribution in their shells and their behavior

Nipah shell disorder, modes of infection, and virulence

The Nipah Virus (NiV) was first isolated during a 1998–9 outbreak in Malaysia. The outbreak initially infected farm pigs and then moved to humans from pigs with a case-fatality rate (CFR) of about 40%. After 2001, regular outbreaks occurred with higher CFRs (~71%, 2001–5, ~93%, 2008–12). The spread arose from drinking virus-laden palm date sap and human-to-human transmission. Intrinsic disorder analysis revealed strong correlation between the percentage of disorder in the N protein and CFR (Regression: r2 = 0.93, p < 0.01, ANOVA: p < 0.01). Distinct disorder and, therefore, genetic differences can be found in all three group of strains. The fact that the transmission modes of the Malaysia strain are different from those of the Bangladesh strains suggests that the correlations may also be linked to the modes of viral transmission. Analysis of the NiV and related viruses suggests links between modes of transmission and disorder of not just the N protein but, also, of M shell protein. The links among shell disorder, transmission modes, and virulence suggest mechanisms by which viruses are attenuated as they passed through different cell hosts from different animal species. These have implications for development of vaccines and epidemiological molecular analytical tools to contain outbreaks

Prostate-associated gene 4 (PAGE4), an intrinsically disordered cancer/testis antigen, is a novel therapeutic target for prostate cancer

Prostate-associated gene 4 (PAGE4) is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein (IDP) that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun. c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer (PCa). Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCa, especially patients with low-risk disease

Rigidity of the Outer Shell Predicted by a Protein Intrinsic Disorder Model Sheds Light on the COVID-19 (Wuhan-2019-nCoV) Infectivity

The world is currently witnessing an outbreak of a new coronavirus spreading quickly across China and affecting at least 24 other countries. With almost 65,000 infected, a worldwide death toll of at least 1370 (as of 14 February 2020), and with the potential to affect up to two-thirds of the world population, COVID-19 is considered by the World Health Organization (WHO) to be a global health emergency. The speed of spread and infectivity of COVID-19 (also known as Wuhan-2019-nCoV) are dramatically exceeding those of the Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). In fact, since September 2012, the WHO has been notified of 2494 laboratory-confirmed cases of infection with MERS-CoV, whereas the 2002–2003 epidemic of SARS affected 26 countries and resulted in more than 8000 cases. Therefore, although SARS, MERS, and COVID-19 are all the result of coronaviral infections, the causes of the coronaviruses differ dramatically in their transmissibility. It is likely that these differences in infectivity of coronaviruses can be attributed to the differences in the rigidity of their shells which can be evaluated using computational tools for predicting intrinsic disorder predisposition of the corresponding viral proteins

Intrinsically disordered proteins link alternative splicing and post-translational modifications to complex cell signaling and regulation

Intrinsically disordered proteins and regions (IDPs and IDRs) lack well-defined tertiary structures, yet carry out various important cellular functions, especially those associated with cell signaling and regulation. In eukaryotes, IDPs and IDRs contain the preferred loci for both alternative splicing (AS) and many post-translational modifications (PTMs). Furthermore, AS and/or PTMs at these loci generally alter the signaling outcomes associated with these IDPs or IDRs, where the functional cooperation of these three features is named the IDP-AS-PTM toolkit. However, the prevalence of such functional modulations remains unknown. Also, the signal-altering mechanisms by which AS, and PTMs modulate function and the extent to which AS and PTMs collaborate in their signaling modulations have not been well defined for particular protein examples. Here we focus on three important signaling and regulatory IDR-containing protein families in humans, namely G-protein coupled receptors (GPCRs), which are transmembrane proteins, the nuclear factors of activated T-cells (NFATs), which are transcription factors (TFs), and the Src family kinases (SFKs), which are signaling enzymes. The goal here is to determine how AS and PTMs individually alter the outcomes of the signaling carried out by the various IDRs and to determine whether AS and PTMs work together to bring about differential cellular responses. We also present data indicating that a wide range of other signaling IDPs or IDRs undergo both AS- and PTM-based modifications, suggesting that they, too, likely take advantage of signal outcome modulations that result from collaboration between these two events. Hence, we propose that the widespread cooperation of IDPs, AS and/or PTMs provides a IDP-AS-PTM toolkit and substantially contributes to the vast complexity of eukaryotic cell signaling systems

A comparative analysis of viral matrix proteins using disorder predictors

Abstract Background A previous study (Goh G.K.-M., Dunker A.K., Uversky V.N. (2008) Protein intrinsic disorder toolbox for comparative analysis of viral proteins. BMC Genomics. 9 (Suppl. 2), S4) revealed that HIV matrix protein p17 possesses especially high levels of predicted intrinsic disorder (PID). In this study, we analyzed the PID patterns in matrix proteins of viruses related and unrelated to HIV-1. Results Both SIVmac and HIV-1 p17 proteins were predicted by PONDR VLXT to be highly disordered with subtle differences containing 50% and 60% disordered residues, respectively. SIVmac is very closely related to HIV-2. A specific region that is predicted to be disordered in HIV-1 is missing in SIVmac. The distributions of PID patterns seem to differ in SIVmac and HIV-1 p17 proteins. A high level of PID for the matrix does not seem to be mandatory for retroviruses, since Equine Infectious Anemia Virus (EIAV), an HIV cousin, has been predicted to have low PID level for the matrix; i.e. its matrix protein p15 contains only 21% PID residues. Surprisingly, the PID percentage and the pattern of predicted disorder distribution for p15 resemble those of the influenza matrix protein M1 (25%). Conclusion Our data might have important implications in the search for HIV vaccines since disorder in the matrix protein might provide a mechanism for immune evasion.</p

INTRINSIC DISORDER, SCAFFOLDS, AND STOCHASTIC MACHINES

poster abstractScaffold proteins bind additional proteins that then carry out multi-step pathways. How do such machines work? Here a new hypothesis is proposed for the complex consisting of axin, two kinases – GSK3β and CK1α, and β-catenin. The pathway involves four discrete phosphorylations of β-catenin by the two kinases. Like many other scaffold proteins, axin is mostly unstructured [1, 2]. With a length of about 800 residues, axin forms two small domains of less than 100 residues each, and uses only a small number of residues, about 20 per interaction, to bind to GSK3β and β-catenin [1], and presumably also to bind to CK1α. Thus, even with the two domains and 3 partners, axin remains mostly unfolded. The hypothesis is that the unstructured axin molecule holds the three globular proteins in very high local concentrations, like three globules on a rope, and that, by random motions, first CK1α and then GSK3β phosphorylate the disordered tail of β-catenin successively four times. The “conformational changes” of axin that lead to acceleration of phosphorylation are neither specific nor coordinated, but rather are entirely stochastic, with stereochemical fit between the enzymes and their targets leading to the correct ordering of the four phosphorylation steps. In this hypothesis, the scaffold protein acts simply as a flexible tether that leads to acceleration of the multiple steps in the pathway by raising the local concentrations of the key components and by allowing the various components the freedom to collide in various orientations until productive collisions result. Thus, the steps of the pathway are carried out by a stochastic machine. This may be a general mechanism for scaffold-based molecular machines