Medicine and Health Sciences Commons^™

Shell Disorder Models Detect That Omicron Has Harder Shells With Attenuation But Is Not A Descendant Of The Wuhan-Hu-1 Sars-Cov-2, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Before the SARS-CoV-2 Omicron variant emergence, shell disorder models (SDM) suggested that an attenuated precursor from pangolins may have entered humans in 2017 or earlier. This was based on a shell disorder analysis of SARS-CoV-1/2 and pangolin-Cov-2017. The SDM suggests that Omicron is attenuated with almost identical N (inner shell) disorder as pangolin-CoV-2017 (N-PID (percentage of intrinsic disorder): 44.8% vs. 44.9%—lower than other variants). The outer shell disorder (M-PID) of Omicron is lower than that of other variants and pangolin-CoV-2017 (5.4% vs. 5.9%). COVID-19-related CoVs have the lowest M-PIDs (hardest outer shell) among all CoVs. This is likely to be …

Looking At The Pathogenesis Of The Rabies Lyssavirus Strain Pasteur Vaccins Through A Prism Of The Disorder-Based Bioinformatics, Surya Dhulipala, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French scientists Louis Pasteur and Émile Roux developed the first vaccine for rabies in 1885. If administered before the virus reaches the brain, the modern rabies vaccine imparts long-lasting immunity to the virus and saves more than 250,000 people every year. However, the rabies virus can suppress the host’s immune response once it has entered the cells of …

Serotonin Promotes Serum Albumin Interaction With The Monomeric Amyloid Β Peptide, Ekaterina A. Litus, Alexei S. Kazakov, Eugenia I. Deryusheva, Ekaterina L. Nemashkalova, Marina P. Shevelyova, Aliya A. Nazipova, Maria E. Permyakova, Elena V. Raznikova, Vladimir N. Uversky, Sergei E. Permyakov

Molecular Medicine Faculty Publications

Prevention of amyloid β peptide (Aβ) deposition via facilitation of Aβ binding to its natural depot, human serum albumin (HSA), is a promising approach to preclude Alzheimer’s disease (AD) onset and progression. Previously, we demonstrated the ability of natural HSA ligands, fatty acids, to improve the affinity of this protein to monomeric Aβ by a factor of 3 (BBRC, 510(2), 248–253). Using plasmon resonance spectroscopy, we show here that another HSA ligand related to AD pathogenesis, serotonin (SRO), increases the affinity of the Aβ monomer to HSA by a factor of 7/17 for Aβ40/Aβ42, respectively. Meanwhile, the structurally homologous SRO …

Hiv Vaccine Mystery And Viral Shell Disorder, Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Hundreds of billions of dollars have been spent for over three decades in the search for an effective human immunodeficiency virus (HIV) vaccine with no success. There are also at least two other sexually transmitted viruses, for which no vaccine is available, the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Traditional textbook explanatory paradigm of rapid mutation of retroviruses cannot adequately address the unavailability of vaccine for many sexually transmissible viruses, since HSV and HCV are DNA and non-retroviral RNA viruses, respectively, whereas effective vaccine for the horsefly-transmitted retroviral cousin of HIV, equine infectious anemia virus (EIAV), …

Prediction Of Disordered Regions And Their Roles In The Anti-Pathogenic And Immunomodulatory Functions Of Butyrophilins, Elrashdy M. Redwan, Ahmed M. Al-Hejin, Hussein A. Almehdar, Abdulrahman Elsaway, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Butyrophilins (BTNs) are a group of the moonlighting proteins, some members of which are secreted in milk. They constitute a large family of structurally similar type 1 transmembrane proteins from the immunoglobulin superfamily. Although the founding member of this family is related to lactation, participating in the secretion, formation and stabilization of milk fat globules, it may also have a cell surface receptor function. Generally, the BTN family members are known to modulate co-stimulatory responses, T cell selection, differentiation, and cell fate determination. Polymorphism of these genes was shown to be associated with the pathology of several human diseases. Despite …

Structural Characterizations Of Phosphorylatable Residues In Transmembrane Proteins From Arabidopsis Thaliana, Bin Xue, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Phosphorylation is a common post-translational modification that plays important roles in a wide range of biochemical and cellular processes. Many enzymes and receptors can be switched “on” or “off” by conformational changes induced by phosphorylation. The phosphorylation process is mediated by a family of enzymes called kinase. Currently, more than 1,000 different kinases have been identified in Arabidopsis thaliana proteome. Kinases interact with each other and with many regulatory proteins forming phosphorylation networks. These phosphorylation networks modulate the signaling processes and control the functions of cells. Normally, kinases phosphorylate serines, threonines, and tyrosines. However, in many proteins, not all of …

Archaic Chaos: Intrinsically Disordered Proteins In Archaea, Bin Xue, Robert W. Williams, Christopher J. Oldfield, A. Keith Dunker, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Background: Many proteins or their regions known as intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) lack unique 3D structure in their native states under physiological conditions yet fulfill key biological functions. Earlier bioinformatics studies showed that IDPs and IDRs are highly abundant in different proteomes and carry out mostly regulatory functions related to molecular recognition and signal transduction. Archaea belong to an intriguing domain of life whose members, being microbes, are characterized by a unique mosaic-like combination of bacterial and eukaryotic properties and include inhabitants of some of the most extreme environments on the planet. With the expansion …

Retro-Morfs: Identifying Protein Binding Sites By Normal And Reverse Alignment And Intrinsic Disorder Prediction, Bin Xue, A. Keith Dunker, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Many cell functions in all living organisms rely on protein-based molecular recognition involving disorder-to-order transitions upon binding by molecular recognition features (MoRFs). A well accepted computational tool for identifying likely protein-protein interactions is sequence alignment. In this paper, we propose the combination of sequence alignment and disorder prediction as a tool to improve the confidence of identifying MoRF-based protein-protein interactions. The method of reverse sequence alignment is also rationalized here as a novel approach for finding additional interaction regions, leading to the concept of a retro-MoRF, which has the reversed sequence of an identified MoRF. The set of retro-MoRF binding …

Protein Disorder In The Human Diseasome: Unfoldomics Of Human Genetic Diseases, Uros Midic, Christopher J. Oldfield, A. Keith Dunker, Zoran Obradovic, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Background: Intrinsically disordered proteins lack stable structure under physiological conditions, yet carry out many crucial biological functions, especially functions associated with regulation, recognition, signaling and control. Recently, human genetic diseases and related genes were organized into a bipartite graph (Goh KI, Cusick ME, Valle D, Childs B, Vidal M, et al. (2007) The human disease network. Proc Natl Acad Sci U S A 104: 8685–8690). This diseasome network revealed several significant features such as the common genetic origin of many diseases.

Methods and findings: We analyzed the abundance of intrinsic disorder in these diseasome network proteins by means of several …

Unfoldomics Of Human Diseases: Linking Protein Intrinsic Disorder With Diseases, Vladimir N. Uversky, Christopher J. Oldfield, Uros Midic, Hongbo Xie, Bin Xue, Slobodan Vucetic, Lilia M. Iakoucheva, Zoran Obradovic, A. Keith Dunker

Molecular Medicine Faculty Publications

Background: Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) lack stable tertiary and/or secondary structure yet fulfills key biological functions. The recent recognition of IDPs and IDRs is leading to an entire field aimed at their systematic structural characterization and at determination of their mechanisms of action. Bioinformatics studies showed that IDPs and IDRs are highly abundant in different proteomes and carry out mostly regulatory functions related to molecular recognition and signal transduction. These activities complement the functions of structured proteins. IDPs and IDRs were shown to participate in both one-to-many and many-to-one signaling. Alternative splicing and posttranslational modifications …

Flexible Nets: Disorder And Induced Fit In The Associations Of P53 And 14-3-3 With Their Partners, Christopher J. Oldfield, Jingwei Meng, Jack Y. Yang, Mary Qu Yang, Vladimir N. Uversky, A. Keith Dunker

Molecular Medicine Faculty Publications

Background: Proteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes. Some of these proteins, called hub proteins or hubs, bind to many different protein partners. Protein intrinsic disorder, via diversity arising from structural plasticity or flexibility, provide a means for hubs to associate with many partners (Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN: Flexible Nets: The roles of intrinsic disorder in protein interaction networks. FEBS J 2005, 272:5129-5148).

Results: Here we present a detailed examination of two divergent examples: 1) p53, which uses different …

The Unfoldomics Decade: An Update On Intrinsically Disordered Proteins, A. Keith Dunker, Christopher J. Oldfield, Jingwei Meng, Pedro Romero, Jack Y. Yang, Jessica Walton Chen, Vladimir Vacic, Zoran Obradovic, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Our first predictor of protein disorder was published just over a decade ago in the Proceedings of the IEEE International Conference on Neural Networks (Romero P, Obradovic Z, Kissinger C, Villafranca JE, Dunker AK (1997) Identifying disordered regions in proteins from amino acid sequence. Proceedings of the IEEE International Conference on Neural Networks, 1: 90–95). By now more than twenty other laboratory groups have joined the efforts to improve the prediction of protein disorder. While the various prediction methodologies used for protein intrinsic disorder resemble those methodologies used for secondary structure prediction, the two types of structures are entirely different. …

Short Linear Motifs Recognized By Sh2, Sh3 And Ser/Thr Kinase Domains Are Conserved In Disordered Protein Regions, Siyun Ren, Vladimir N. Uversky, Zhengjun Chen, A. Keith Dunker, Zoran Obradovic

Molecular Medicine Faculty Publications

Background: Protein interactions are essential for most cellular functions. Interactions mediated by domains that appear in a large number of proteins are of particular interest since they are expected to have an impact on diversities of cellular processes such as signal transduction and immune response. Many well represented domains recognize and bind to primary sequences less than 10 amino acids in length called Short Linear Motifs (SLiMs).

Results: In this study, we systematically studied the evolutionary conservation of SLiMs recognized by SH2, SH3 and Ser/Thr Kinase domains in both ordered and disordered protein regions. Disordered protein regions are protein sequences …

Composition Profiler: A Tool For Discovery And Visualization Of Amino Acid Composition Differences, Vladimir Vacic, Vladimir N. Uversky, A. Keith Dunker, Stefano Lonardi

Molecular Medicine Faculty Publications

Background: Composition Profiler is a web-based tool for semi-automatic discovery of enrichment or depletion of amino acids, either individually or grouped by their physico-chemical or structural properties.

Results: The program takes two samples of amino acids as input: a query sample and a reference sample. The latter provides a suitable background amino acid distribution, and should be chosen according to the nature of the query sample, for example, a standard protein database (e.g. SwissProt, PDB), a representative sample of proteins from the organism under study, or a group of proteins with a contrasting functional annotation. The results of the analysis …