scholarly journals Intrinsically disordered proteins drive enamel formation via an evolutionarily conserved self-assembly motif

2017 ◽  
Vol 114 (9) ◽  
pp. E1641-E1650 ◽  
Author(s):  
Tomas Wald ◽  
Frantisek Spoutil ◽  
Adriana Osickova ◽  
Michaela Prochazkova ◽  
Oldrich Benada ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Self Assembly ◽  
Intrinsically Disordered Proteins ◽  
Organic Matrix ◽  
Matrix Proteins ◽  
Disordered Proteins ◽  
Order Structure ◽  
Type I ◽  
Intrinsically Disordered ◽  
Evolutionarily Conserved

The formation of mineralized tissues is governed by extracellular matrix proteins that assemble into a 3D organic matrix directing the deposition of hydroxyapatite. Although the formation of bones and dentin depends on the self-assembly of type I collagen via the Gly-X-Y motif, the molecular mechanism by which enamel matrix proteins (EMPs) assemble into the organic matrix remains poorly understood. Here we identified a Y/F-x-x-Y/L/F-x-Y/F motif, evolutionarily conserved from the first tetrapods to man, that is crucial for higher order structure self-assembly of the key intrinsically disordered EMPs, ameloblastin and amelogenin. Using targeted mutations in mice and high-resolution imaging, we show that impairment of ameloblastin self-assembly causes disorganization of the enamel organic matrix and yields enamel with disordered hydroxyapatite crystallites. These findings define a paradigm for the molecular mechanism by which the EMPs self-assemble into supramolecular structures and demonstrate that this process is crucial for organization of the organic matrix and formation of properly structured enamel.

scholarly journals Lipid-Chaperone Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins

2020 ◽  
Vol 11 (24) ◽  
pp. 4336-4350 ◽  
Author(s):  
Michele F. Sciacca ◽  
Fabio Lolicato ◽  
Carmelo Tempra ◽  
Federica Scollo ◽  
Bikash R. Sahoo ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Membrane Disruption ◽  
Intrinsically Disordered

scholarly journals NLIP and HAD-like Domains of Pah1 and Lipin 1 Phosphatidate Phosphatases Are Essential for Their Catalytic Activities

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5470
Author(s):  
Wei-Hsin Hsu ◽  
Yi-Hao Huang ◽  
Pin-Ru Chen ◽  
Lu-Sheng Hsieh
Keyword(s):  
Catalytic Activity ◽  
Intrinsically Disordered Proteins ◽  
Protein Solubility ◽  
Disordered Proteins ◽  
Haloacid Dehalogenase ◽  
Catalytic Activities ◽  
Intrinsically Disordered ◽  
Conserved Regions ◽  
Evolutionarily Conserved ◽  
Lipin 1

Saccharomyces cerevisiae Pah1 phosphatidate phosphatase (PAP) catalyzes the dephosphorylation of phosphatidate to yield diacylglycerol, controlling phospholipids and triacylglycerol metabolisms. Pah1 and human Lipin 1 are intrinsically disordered proteins with 56% and 43% unfolded regions, respectively. Truncation analysis of the conserved and non-conserved regions showed that N- and C-conserved regions are essential for the catalytic activity of Pah1. PAP activities can be detected in the conserved N-terminal Lipin (NLIP) domain and C-terminal Lipin (CLIP)/haloacid dehalogenase (HAD)-like domain of Pah1 and Lipin 1, suggesting that the evolutionarily conserved domains are essential for the catalytic activity. The removal of disordered hydrophilic regions drastically reduced the protein solubility of Pah1. Thioredoxin is an efficient fusion protein for production of soluble NLIP–HAD recombinant proteins in Escherichia coli.

scholarly journals Structure of the 5′ Untranslated Region of Enteroviral Genomic RNA

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Bejan Mahmud ◽  
Christopher M. Horn ◽  
William E. Tapprich
Keyword(s):  
Untranslated Region ◽  
Intrinsically Disordered Proteins ◽  
Structural Information ◽  
Disordered Proteins ◽  
Type I ◽  
Genomic Rna ◽  
Entry Site ◽  
Specific Chemical ◽  
Intrinsically Disordered ◽  
Viral Virulence

ABSTRACT Enteroviral RNA genomes share a long, highly structured 5′ untranslated region (5′ UTR) containing a type I internal ribosome entry site (IRES). The 5′ UTR is composed of stably folded RNA domains connected by unstructured RNA regions. Proper folding and functioning of the 5′ UTR underlies the efficiency of viral replication and also determines viral virulence. We have characterized the structure of 5′ UTR genomic RNA from coxsackievirus B3 using selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) and base-specific chemical probes in solution. Our results revealed novel structural features, including realignment of major domains, newly identified long-range interactions, and an intrinsically disordered connecting region. Together, these newly identified features contribute to a model for enteroviral 5′ UTRs with type I IRES elements that links structure to function during the hierarchical processes directed by genomic RNA during viral infection. IMPORTANCE Enterovirus infections are responsible for human diseases, including myocarditis, pancreatitis, acute flaccid paralysis, and poliomyelitis. The virulence of these viruses depends on efficient recognition of the RNA genome by a large family of host proteins and protein synthesis factors, which in turn relies on the three-dimensional folding of the first 750 nucleotides of the molecule. Structural information about this region of the genome, called the 5′ untranslated region (5′ UTR), is needed to assist in the process of vaccine and antiviral development. This work presents a model for the structure of the enteroviral 5′ UTR. The model includes an RNA element called an intrinsically disordered RNA region (IDRR). Intrinsically disordered proteins (IDPs) are well known, but correlates in RNA have not been proposed. The proposed IDRR is a 20-nucleotide region, long known for its functional importance, where structural flexibility helps explain recognition by factors controlling multiple functional states.

scholarly journals ADAPs intrinsically disordered region is an actin sponge regulating T cell motility

2021 ◽  
Author(s):  
Nirdosh Dadwal ◽  
Janine Degen ◽  
Jana Sticht ◽  
Tarek Hilal ◽  
Tatjana Wegner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Self Assembly ◽  
Actin Polymerization ◽  
Intrinsically Disordered Proteins ◽  
Critical Concentration ◽  
Cell Receptor ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region

Intrinsically disordered proteins (IDPs) play a vital role in biological processes that rely on transient molecular compartmentation1. In T cells, the dynamic switching between migration and adhesion mandates a high degree of plasticity in the interplay of adhesion and signaling molecules with the actin cytoskeleton2,3. Here, we show that the N-terminal intrinsically disordered region (IDR) of adhesion- and degranulation-promoting adapter protein (ADAP) acts as a multipronged scaffold for G- and F-actin, thereby promoting actin polymerization and bundling. Positively charged motifs, along a sequence of at least 200 amino acids, interact with both longitudinal sides of G-actin in a promiscuous manner. These polymorphic interactions with ADAP become constrained to one side once F-actin is formed. Actin polymerization by ADAP acts in synergy with a capping protein but competes with cofilin. In T cells, ablation of ADAP impairs adhesion and migration with a time-dependent reduction of the F-actin content in response to chemokine or T cell receptor (TCR) engagement. Our data suggest that IDR-assisted molecular crowding of actin above the critical concentration defines a new mechanism to regulate cytoskeletal dynamics. The principle of IDRs serving as molecular sponges to facilitate regulated self-assembly of filament-forming proteins might be a general phenomenon.

scholarly journals Amyloidogenic Intrinsically Disordered Proteins: New Insights into Their Self-Assembly and Their Interaction with Membranes

Life ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 144 ◽  
Author(s):  
Federica Scollo ◽  
Carmelo La Rosa
Keyword(s):  
Self Assembly ◽  
Protein Transport ◽  
Intrinsically Disordered Proteins ◽  
Interaction Mechanism ◽  
Type Ii Diabetes Mellitus ◽  
Disordered Proteins ◽  
Future Perspective ◽  
Main Role ◽  
Membrane Phospholipids ◽  
Intrinsically Disordered

Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins’ family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer’s, Type II Diabetes Mellitus, Parkinson’s, and Creutzfeldt–Jakob’s diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers.

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