Medicine and Health Sciences Commons^™

Theater In The Self-Cleaning Cell: Intrinsically Disordered Proteins Or Protein Regions Acting With Membranes In Autophagy, Hana Popelka, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Intrinsically disordered proteins and protein regions (IDPs/IDPRs) are mainly involved in signaling pathways, where fast regulation, temporal interactions, promiscuous interactions, and assemblies of structurally diverse components including membranes are essential. The autophagy pathway builds, de novo, a membrane organelle, the autophagosome, using carefully orchestrated interactions between proteins and lipid bilayers. Here, we discuss molecular mechanisms related to the protein disorder-based interactions of the autophagy machinery with membranes. We describe not only membrane binding phenomenon, but also examples of membrane remodeling processes including membrane tethering, bending, curvature sensing, and/or fragmentation of membrane organelles such as the endoplasmic reticulum, which is an …

On The Roles Of Intrinsically Disordered Proteins And Regions In Cell Communication And Signaling, Sarah E. Bondos, A. Keith Dunker, Vladimir N. Uversky

Molecular Medicine Faculty Publications

For proteins, the sequence → structure → function paradigm applies primarily to enzymes, transmembrane proteins, and signaling domains. This paradigm is not universal, but rather, in addition to structured proteins, intrinsically disordered proteins and regions (IDPs and IDRs) also carry out crucial biological functions. For these proteins, the sequence → IDP/IDR ensemble → function paradigm applies primarily to signaling and regulatory proteins and regions. Often, in order to carry out function, IDPs or IDRs cooperatively interact, either intra- or inter-molecularly, with structured proteins or other IDPs or intermolecularly with nucleic acids. In this IDP/IDR thematic collection published in Cell Communication …

The Participation Of The Intrinsically Disordered Regions Of The Bhlh-Pas Transcription Factors In Disease Development, Marta Kolonko-Adamska, Vladimir N. Uversky, Beata Greb-Markiewicz

Molecular Medicine Faculty Publications

The basic helix–loop–helix/Per-ARNT-SIM (bHLH-PAS) proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, ranging from differentiation and development control by oxygen and toxins sensing to circadian clock setting. In addition to the well-preserved DNA-binding bHLH and PAS domains, bHLH-PAS proteins contain long intrinsically disordered C-terminal regions, responsible for regulation of their activity. Our aim was to analyze the potential connection between disordered regions of the bHLH-PAS transcription factors, post-transcriptional modifications and liquid-liquid phase separation, in the context of disease-associated missense mutations. Highly flexible disordered regions, enriched in short motives which …

A Comprehensive Survey Of The Roles Of Highly Disordered Proteins In Type 2 Diabetes, Zhihua Du, Vladimir N. Uversky

Molecular Medicine Faculty Publications

Type 2 diabetes mellitus (T2DM) is a chronic and progressive disease that is strongly associated with hyperglycemia (high blood sugar) related to either insulin resistance or insufficient insulin production. Among the various molecular events and players implicated in the manifestation and development of diabetes mellitus, proteins play several important roles. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database has information on 34 human proteins experimentally shown to be related to the T2DM pathogenesis. It is known that many proteins associated with different human maladies are intrinsically disordered as a whole, or contain intrinsically disordered regions. The presented study shows …

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 …

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 …

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 …