Intrinsically Disordered Proteins and Their Environment: Effects of Strong Denaturants, Temperature, pH, Counter Ions, Membranes, Binding Partners, Osmolytes, and Macromolecular Crowding

2009 ◽  
Vol 28 (7-8) ◽  
pp. 305-325 ◽  
Author(s):  
Vladimir N. Uversky
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Macromolecular Crowding ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Environment Effects ◽  
Binding Partners ◽  
Counter Ions

scholarly journals The Disordered Cellular Multi-Tasker WIP and Its Protein–Protein Interactions: A Structural View

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1084 ◽  
Author(s):  
Chana G. Sokolik ◽  
Nasrin Qassem ◽  
Jordan H. Chill
Keyword(s):  
Protein Interactions ◽  
Cell Biology ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Actin Binding ◽  
Structural Description ◽  
Protein Protein Interactions ◽  
Intrinsically Disordered ◽  
Terminal Domain ◽  
Binding Partners

WASp-interacting protein (WIP), a regulator of actin cytoskeleton assembly and remodeling, is a cellular multi-tasker and a key member of a network of protein–protein interactions, with significant impact on health and disease. Here, we attempt to complement the well-established understanding of WIP function from cell biology studies, summarized in several reviews, with a structural description of WIP interactions, highlighting works that present a molecular view of WIP’s protein–protein interactions. This provides a deeper understanding of the mechanisms by which WIP mediates its biological functions. The fully disordered WIP also serves as an intriguing example of how intrinsically disordered proteins (IDPs) exert their function. WIP consists of consecutive small functional domains and motifs that interact with a host of cellular partners, with a striking preponderance of proline-rich motif capable of interactions with several well-recognized binding partners; indeed, over 30% of the WIP primary structure are proline residues. We focus on the binding motifs and binding interfaces of three important WIP segments, the actin-binding N-terminal domain, the central domain that binds SH3 domains of various interaction partners, and the WASp-binding C-terminal domain. Beyond the obvious importance of a more fundamental understanding of the biology of this central cellular player, this approach carries an immediate and highly beneficial effect on drug-design efforts targeting WIP and its binding partners. These factors make the value of such structural studies, challenging as they are, readily apparent.

scholarly journals Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins

2020 ◽  
Vol 295 (51) ◽  
pp. 17698-17712
Author(s):  
Elin Karlsson ◽  
Cristina Paissoni ◽  
Amanda M. Erkelens ◽  
Zeinab A. Tehranizadeh ◽  
Frieda A. Sorgenfrei ◽  
...  
Keyword(s):  
Transition State ◽  
Intrinsically Disordered Proteins ◽  
Intrinsically Disordered Protein ◽  
Disordered Proteins ◽  
Hydrophobic Contact ◽  
Intrinsically Disordered ◽  
Binding Partners ◽  
Multiple Alternative ◽  
Transient Interactions ◽  
Affinity Interaction

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

scholarly journals IDEAL in 2014 illustrates interaction networks composed of intrinsically disordered proteins and their binding partners

2013 ◽  
Vol 42 (D1) ◽  
pp. D320-D325 ◽  
Author(s):  
Satoshi Fukuchi ◽  
Takayuki Amemiya ◽  
Shigetaka Sakamoto ◽  
Yukiko Nobe ◽  
Kazuo Hosoda ◽  
...  
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Interaction Networks ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Binding Partners

scholarly journals Prediction of the effect of pH on the aggregation and conditional folding of intrinsically disordered proteins with SolupHred and DispHred.

2021 ◽  
Author(s):  
Valentin Iglesias ◽  
Carlos Pintado-Grima ◽  
Jaime Santos ◽  
Marc Fornt ◽  
Salvador Ventura
Keyword(s):  
Conformational Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Net Charge ◽  
Software Applications ◽  
Intrinsically Disordered ◽  
Binding Partners ◽  
Dissolved Ions ◽  
Ph Dependent ◽  
User Friendly

Proteins microenvironments modulate their structures. Binding partners, organic molecules, or dissolved ions can alter the protein's compaction, inducing aggregation or order-disorder conformational transitions. Surprisingly, bioinformatic platforms often disregard the protein context in their modeling. In recent work, we proposed that modeling how pH affects protein net charge and hydrophobicity might allow us to forecast pH-dependent aggregation and conditional disorder in intrinsically disordered proteins (IDPs). As these approaches showed remarkable success in recapitulating the available bibliographical data, we made these prediction methods available for the scientific community as two user-friendly web servers. SolupHred is the first dedicated software to predict pH-dependent aggregation, and DispHred is the first pH-dependent predictor of protein disorder. Here we dissect the features of these two software applications to train and assist scientists in studying pH-dependent conformational changes in IDPs.

scholarly journals On the specificity of protein–protein interactions in the context of disorder

2021 ◽  
Vol 478 (11) ◽  
pp. 2035-2050
Author(s):  
Kaare Teilum ◽  
Johan G. Olsen ◽  
Birthe B. Kragelund
Keyword(s):  
Protein Interactions ◽  
Intrinsically Disordered Proteins ◽  
Globular Proteins ◽  
Disordered Proteins ◽  
Protein Protein Interactions ◽  
Binding Motifs ◽  
Intrinsically Disordered ◽  
Binding Partners ◽  
Trimer Formation ◽  
Definition Of

With the increased focus on intrinsically disordered proteins (IDPs) and their large interactomes, the question about their specificity — or more so on their multispecificity — arise. Here we recapitulate how specificity and multispecificity are quantified and address through examples if IDPs in this respect differ from globular proteins. The conclusion is that quantitatively, globular proteins and IDPs are similar when it comes to specificity. However, compared with globular proteins, IDPs have larger interactome sizes, a phenomenon that is further enabled by their flexibility, repetitive binding motifs and propensity to adapt to different binding partners. For IDPs, this adaptability, interactome size and a higher degree of multivalency opens for new interaction mechanisms such as facilitated exchange through trimer formation and ultra-sensitivity via threshold effects and ensemble redistribution. IDPs and their interactions, thus, do not compromise the definition of specificity. Instead, it is the sheer size of their interactomes that complicates its calculation. More importantly, it is this size that challenges how we conceptually envision, interpret and speak about their specificity.

Intrinsic disorder in proteins: a challenge for (un)structural biology met by ion mobility–mass spectrometry

2012 ◽  
Vol 40 (5) ◽  
pp. 1021-1026 ◽  
Author(s):  
Ewa Jurneczko ◽  
Faye Cruickshank ◽  
Massimiliano Porrini ◽  
Penka Nikolova ◽  
Iain D.G. Campuzano ◽  
...  
Keyword(s):  
Ion Mobility ◽  
Intrinsically Disordered Proteins ◽  
Three Dimensional ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
New Methods ◽  
Binding Partners ◽  
Nanoelectrospray Ionization ◽  
And Function

The link between structure and function of a given protein is a principal tenet of biology. The established approach to understand the function of a protein is to ‘solve’ its structure and subsequently investigate interactions between the protein and its binding partners. However, structure determination via crystallography or NMR is challenging for proteins where localized regions or even their entire structure fail to fold into a three-dimensional form. These so called IDPs (intrinsically disordered proteins) or intrinsically disordered regions constitute up to 40% of all expressed proteins, and a much higher percentage in proteins involved in the proliferation of cancer. For these proteins, there is a need to develop new methods for structural characterization which exploit their biophysical properties. IM (ion mobility)–MS is uniquely able to examine both absolute conformation(s), populations of conformation and also conformational change, and is therefore highly applicable to the study of IDPs. The present article details the technique of IM–MS and illustrates its use in assessing the relative disorder of the wild-type p53 DNA-core-binding domain of cellular tumour antigen p53. The IM data were acquired on a Waters Synapt HDMS instrument following nESI (nanoelectrospray ionization) from ‘native’ and low-pH solution conditions.

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