Medicine and Health Sciences Commons^™

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 …

Substance P Increases Cell-Surface Expression Of Cd74 (Receptor For Macrophage Migration Inhibitory Factor): In Vivo Biotinylation Of Urothelial Cell-Surface Proteins, Katherine L. Meyer-Siegler, Shen-Ling Xia, Pedro L. Vera

Molecular Medicine Faculty Publications

Macrophage migration inhibitory factor (MIF), an inflammatory cytokine, and its receptor CD74 are upregulated by bladder inflammation. MIF-mediated signal transduction involves binding to cell-surface CD74, this study documents, in vivo, MIF-CD74 interactions at the urothelial cell surface. N-hydroxysulfosuccinimide biotin ester-labeled surface urothelial proteins in rats treated either with saline or substance P (SP, 40 μg/kg). The bladder was examined by histology and confocal microscopy. Biotinylated proteins were purified by avidin agarose, immunoprecipitated with anti-MIF or anti-CD74 antibodies, and detected with strepavidin-HRP. Only superficial urothelial cells were biotinylated. These cells contained a biotinylated MIF/CD74 cell-surface complex that was increased in …

The Mysterious Unfoldome: Structureless, Underappreciated, Yet Vital Part Of Any Given Proteome, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Contrarily to the general believe, many biologically active proteins lack stable tertiary and/or secondary structure under physiological conditions in vitro. These intrinsically disordered proteins (IDPs) are highly abundant in nature and many of them are associated with various human diseases. The functional repertoire of IDPs complements the functions of ordered proteins. Since IDPs constitute a significant portion of any given proteome, they can be combined in an unfoldome; which is a portion of the proteome including all IDPs (also known as natively unfolded proteins, therefore, unfoldome), and describing their functions, structures, interactions, evolution, and so forth. Amino acid sequence and …

Influence Of Sequence Changes And Environment On Intrinsically Disordered Proteins, Amrita Mohan, Vladimir N. Uversky, Predrag Radivojac

Molecular Medicine Faculty Publications

Many large-scale studies on intrinsically disordered proteins are implicitly based on the structural models deposited in the Protein Data Bank. Yet, the static nature of deposited models supplies little insight into variation of protein structure and function under diverse cellular and environmental conditions. While the computational predictability of disordered regions provides practical evidence that disorder is an intrinsic property of proteins, the robustness of disordered regions to changes in sequence or environmental conditions has not been systematically studied. We analyzed intrinsically disordered regions in the same or similar proteins crystallized independently and studied their sensitivity to changes in protein sequence …

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 …

Protein Intrinsic Disorder And Influenza Virulence: The 1918 H1n1 And H5n1 Viruses, Gerard Kian-Meng Goh, A. Keith Dunker, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Background: The 1918 H1N1 virus was a highly virulent strain that killed 20–50 million people. The cause of its virulence remains poorly understood.

Methods: Intrinsic disorder predictor PONDR® VLXT was used to compare various influenza subtypes and strains. Three-dimensional models using data from X-ray crystallographic studies annotated with disorder prediction were used to characterize the proteins.

Results: The protein of interest is hemagglutin (HA), which is a surface glycoprotein that plays a vital role in viral entry. Distinct differences between HA proteins of the virulent and non-virulent strains are seen, especially in the region near residues 68–79 of the HA2. …