The Desmoglein-Specific Cytoplasmic Region Is Intrinsically Disordered in Solution and Interacts with Multiple Desmosomal Protein Partners

2009 ◽  
Vol 386 (2) ◽  
pp. 531-543 ◽  
Author(s):  
Keiichiro Kami ◽  
Martyn Chidgey ◽  
Timothy Dafforn ◽  
Michael Overduin
Keyword(s):  
Cytoplasmic Region ◽  
Intrinsically Disordered ◽  
Protein Partners ◽  
Desmosomal Protein

scholarly journals Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration

2021 ◽  
Author(s):  
Srinivas Ayyadevara ◽  
Akshatha Ganne ◽  
Meenakshisundaram Balasubramaniam ◽  
Robert J. Shmookler Reis
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Protein Complexes ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Physiological Processes ◽  
Protein Partners ◽  
And Function ◽  
Computational Analyses ◽  
Disordered Regions

AbstractA protein’s structure is determined by its amino acid sequence and post-translational modifications, and provides the basis for its physiological functions. Across all organisms, roughly a third of the proteome comprises proteins that contain highly unstructured or intrinsically disordered regions. Proteins comprising or containing extensive unstructured regions are referred to as intrinsically disordered proteins (IDPs). IDPs are believed to participate in complex physiological processes through refolding of IDP regions, dependent on their binding to a diverse array of potential protein partners. They thus play critical roles in the assembly and function of protein complexes. Recent advances in experimental and computational analyses predicted multiple interacting partners for the disordered regions of proteins, implying critical roles in signal transduction and regulation of biological processes. Numerous disordered proteins are sequestered into aggregates in neurodegenerative diseases such as Alzheimer’s disease (AD) where they are enriched even in serum, making them good candidates for serum biomarkers to enable early detection of AD.

scholarly journals Structural and Biophysical Insights into the Function of the Intrinsically Disordered Myc Oncoprotein

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1038 ◽  
Author(s):  
Marie-Eve Beaulieu ◽  
Francisco Castillo ◽  
Laura Soucek
Keyword(s):  
Cancer Biology ◽  
Leucine Zipper ◽  
Intrinsically Disordered ◽  
Helix Loop Helix ◽  
Folded Structure ◽  
Protein Partners ◽  
Molecular Determinants ◽  
Binding Pockets ◽  
Cumulative Knowledge ◽  
Redundant Role

Myc is a transcription factor driving growth and proliferation of cells and involved in the majority of human tumors. Despite a huge body of literature on this critical oncogene, our understanding of the exact molecular determinants and mechanisms that underlie its function is still surprisingly limited. Indubitably though, its crucial and non-redundant role in cancer biology makes it an attractive target. However, achieving successful clinical Myc inhibition has proven challenging so far, as this nuclear protein is an intrinsically disordered polypeptide devoid of any classical ligand binding pockets. Indeed, Myc only adopts a (partially) folded structure in some contexts and upon interacting with some protein partners, for instance when dimerizing with MAX to bind DNA. Here, we review the cumulative knowledge on Myc structure and biophysics and discuss the implications for its biological function and the development of improved Myc inhibitors. We focus this biophysical walkthrough mainly on the basic region helix–loop–helix leucine zipper motif (bHLHLZ), as it has been the principal target for inhibitory approaches so far.

scholarly journals The ‘Shape-Shifter’ Peptide from the Disulphide Isomerase PmScsC Shows Context-Dependent Conformational Preferences

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 642
Author(s):  
Lorna J. Smith ◽  
Chloe W. Green ◽  
Christina Redfield
Keyword(s):  
Crystal Structures ◽  
Intrinsically Disordered Proteins ◽  
Catalytic Domain ◽  
Helical Structure ◽  
Md Simulations ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Linker Peptide ◽  
Protein Partners ◽  
Context Dependent

Multiple crystal structures of the homo-trimeric protein disulphide isomerase PmScsC reveal that the peptide which links the trimerization stalk and catalytic domain can adopt helical, β-strand and loop conformations. This region has been called a ‘shape-shifter’ peptide. Characterisation of this peptide using NMR experiments and MD simulations has shown that it is essentially disordered in solution. Analysis of the PmScsC crystal structures identifies the role of intermolecular contacts, within an assembly of protein molecules, in stabilising the different linker peptide conformations. These context-dependent conformational properties may be important functionally, allowing for the binding and disulphide shuffling of a variety of protein substrates to PmScsC. They also have a relevance for our understanding of protein aggregation and misfolding showing how intermolecular quaternary interactions can lead to β-sheet formation by a sequence that in other contexts adopts a helical structure. This ‘shape-shifting’ peptide region within PmScsC is reminiscent of one-to-many molecular recognition features (MoRFs) found in intrinsically disordered proteins which are able to adopt different conformations when they fold upon binding to their protein partners.

Intrinsically disordered proteins: lessons from colicins

2012 ◽  
Vol 40 (6) ◽  
pp. 1534-1538 ◽  
Author(s):  
Oliver Hecht ◽  
Colin Macdonald ◽  
Geoffrey R. Moore
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Structural Features ◽  
Intramolecular Interactions ◽  
Disordered Proteins ◽  
Target Cells ◽  
Bacterial Cells ◽  
Intrinsically Disordered ◽  
Self Recognition ◽  
Protein Partners

Defining structural features of IDPs (intrinsically disordered proteins) and relating these to biological function requires characterization of their dynamical properties. In the present paper, we review what is known about the IDPs of colicins, protein antibiotics that use their IDPs to enter bacterial cells. The structurally characterized colicin IDPs we consider contain linear binding epitopes for proteins within their target cells that the colicin hijacks during entry. We show that these binding epitopes take part in intramolecular interactions in the absence of protein partners, i.e. self-recognition, and consider the structural origins of this and its functional implications. We suggest that self-recognition is common in other IDPs that contain similar types of binding epitopes.

scholarly journals Phosphorylation in the intrinsically disordered region of F-BAR protein Imp2 regulates its contractile ring recruitment

2021 ◽  
Author(s):  
Alaina H. Willet ◽  
Maya G. Igarashi ◽  
Jun-Song Chen ◽  
Rahul Bhattacharjee ◽  
Liping Ren ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Contractile Ring ◽  
Casein Kinase 1 ◽  
Protein Levels ◽  
Intrinsically Disordered ◽  
Division Site ◽  
Protein Partners ◽  
Intrinsically Disordered Region ◽  
And Function

The F-BAR protein Imp2 is an important contributor to cytokinesis in the fission yeast, Schizosaccharomyces pombe. Because cell cycle regulated phosphorylation of the central intrinsically disordered region (IDR) of the Imp2 paralog, Cdc15, controls Cdc15 oligomerization state, localization, and ability to bind protein partners, we investigated whether Imp2 is similarly phosphoregulated. We found that Imp2 is endogenously phosphorylated on 28 sites within its IDR with the bulk of phosphorylation being constitutive. In vitro, casein kinase 1 (CK1) Hhp1 and Hhp2 can phosphorylate 17 sites and Cdk1 the remaining 11 sites. Mutations that prevent Cdk1 phosphorylation result in precocious Imp2 recruitment to the cell division site, and mutations designed to mimic these phosphorylation events delay Imp2 CR accumulation. Mutations that eliminated CK1 phosphorylation sites allowed CR sliding, and phosphomimetic substitutions at these sites reduced Imp2 protein levels and slowed CR constriction. Thus, like Cdc15, the Imp2 IDR is phosphorylated at many sites by multiple kinases. In contrast to Cdc15, for which phosphorylation plays a major cell cycle regulatory role, Imp2 phosphorylation is primarily constitutive with milder effects on localization and function.

scholarly journals Intrinsically disordered HAX-1 regulates Ca2+ cycling by interacting with lipid membranes and the phospholamban cytoplasmic region

2020 ◽  
Vol 1862 (1) ◽  
pp. 183034 ◽  
Author(s):  
Erik K. Larsen ◽  
Daniel K. Weber ◽  
Songlin Wang ◽  
Tata Gopinath ◽  
Daniel J. Blackwell ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Cytoplasmic Region ◽  
Intrinsically Disordered

scholarly journals Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction

2020 ◽  
Vol 21 (19) ◽  
pp. 7058
Author(s):  
Hajar Miranzadeh Mahabadi ◽  
Changiz Taghibiglou
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Physiological Role ◽  
Cellular Prion Protein ◽  
Interacting Protein ◽  
Intrinsically Disordered ◽  
Outer Leaflet ◽  
Protein Partners ◽  
Wide Range ◽  
The Central Nervous System

Cellular prion protein (PrPc) is a small glycosylphosphatidylinositol (GPI) anchored protein most abundantly found in the outer leaflet of the plasma membrane (PM) in the central nervous system (CNS). PrPc misfolding causes neurodegenerative prion diseases in the CNS. PrPc interacts with a wide range of protein partners because of the intrinsically disordered nature of the protein’s N-terminus. Numerous studies have attempted to decipher the physiological role of the prion protein by searching for proteins which interact with PrPc. Biochemical characteristics and biological functions both appear to be affected by interacting protein partners. The key challenge in identifying a potential interacting partner is to demonstrate that binding to a specific ligand is necessary for cellular physiological function or malfunction. In this review, we have summarized the intracellular and extracellular interacting partners of PrPc and potential consequences of their binding. We also briefly describe prion disease-related mutations at the end of this review.

scholarly journals Pneumoviral Phosphoprotein, a Multidomain Adaptor-Like Protein of Apparent Low Structural Complexity and High Conformational Versatility

2021 ◽  
Vol 22 (4) ◽  
pp. 1537
Author(s):  
Christophe Cardone ◽  
Claire-Marie Caseau ◽  
Nelson Pereira ◽  
Christina Sizun
Keyword(s):  
3D Structure ◽  
Structural Complexity ◽  
Intrinsically Disordered Protein ◽  
Structural Features ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Protein ◽  
Protein Partners ◽  
P Proteins ◽  
Oligomerization Domain

Mononegavirales phosphoproteins (P) are essential co-factors of the viral polymerase by serving as a linchpin between the catalytic subunit and the ribonucleoprotein template. They have highly diverged, but their overall architecture is conserved. They are multidomain proteins, which all possess an oligomerization domain that separates N- and C-terminal domains. Large intrinsically disordered regions constitute their hallmark. Here, we exemplify their structural features and interaction potential, based on the Pneumoviridae P proteins. These P proteins are rather small, and their oligomerization domain is the only part with a defined 3D structure, owing to a quaternary arrangement. All other parts are either flexible or form short-lived secondary structure elements that transiently associate with the rest of the protein. Pneumoviridae P proteins interact with several viral and cellular proteins that are essential for viral transcription and replication. The combination of intrinsic disorder and tetrameric organization enables them to structurally adapt to different partners and to act as adaptor-like platforms to bring the latter close in space. Transient structures are stabilized in complex with protein partners. This class of proteins gives an insight into the structural versatility of non-globular intrinsically disordered protein domains.

scholarly journals The Unconventional Self-Cleavage of Selenoprotein K

2021 ◽  
Author(s):  
Rujin Cheng ◽  
Jun Liu ◽  
Martin Forstner ◽  
George Woodward ◽  
Elmer Heppard ◽  
...  
Keyword(s):  
Intrinsically Disordered Protein ◽  
Cellular Functions ◽  
Peptide Bonds ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
Catalytic Function ◽  
Protein Partners ◽  
Selenoprotein K

Through known association with other proteins, human selenoprotein K (selenok) is currently implicated in the palmitoylation of proteins, degradation of misfolded proteins, innate immune response, and the life cycle of SARS-CoV-2 virus. However, neither the catalytic function of selenok's selenocysteine (Sec), which, curiously, resides in an intrinsically disordered protein segment nor selenok's specific role in these pathways are known to date. This report casts these questions in a new light as it describes that selenok is able -both in vitro and in vivo- to cleave some of its own peptide bonds. The cleavages not only release selenok segments that contain its reactive Sec, but as the specific cleavage sites were identified, they proved to cluster tightly near sites through which selenok interacts with protein partners. Furthermore, it is shown that selenok's cleavage activity is neither restricted to itself nor promiscuous but selectively extends to at least one of its protein partners. Together, selenok's cleavage ability and its features have all hallmarks of a regulatory mechanism that could play a central role in selenok's associations with other proteins and its cellular functions overall.

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