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 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 Evolutionarily Conserved Network Properties of Intrinsically Disordered Proteins

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0126729 ◽  
Author(s):  
Nivedita Rangarajan ◽  
Prakash Kulkarni ◽  
Sridhar Hannenhalli
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered ◽  
Evolutionarily Conserved ◽  
Network Properties

scholarly journals Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Zhengjian Zhang ◽  
Zarko Boskovic ◽  
Mahmud M Hussain ◽  
Wenxin Hu ◽  
Carla Inouye ◽  
...  
Keyword(s):  
Transcription Initiation ◽  
Intrinsically Disordered Proteins ◽  
De Novo ◽  
Disordered Proteins ◽  
Specific Chemical ◽  
Pol Ii ◽  
3 Dimensional ◽  
Intrinsically Disordered ◽  
Evolutionarily Conserved ◽  
Eukaryotic Proteomes

Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions.

Sequence Specificity Despite Intrinsic Disorder: How a Disease-Associated Val/Met Polymorphism Shifts Tertiary Interactions in a Long Disordered Protein

2019 ◽  
Author(s):  
Ruchi Lohia ◽  
Reza Salari ◽  
Grace Brannigan
Keyword(s):  
Secondary Structure ◽  
Electrostatic Interactions ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Sequence Specificity ◽  
Intrinsically Disordered ◽  
Specific Effects ◽  
Heterogeneous Polymer ◽  
Non Local ◽  
Dynamics Simulations

<div>The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) encodes a hydrophobic-to-hydrophobic mutation at the midpoint of the prodomain of precursor brain-derived neurotrophic factor (BDNF), one of the earliest SNPs to be associated with neuropsychiatric disorders, for which the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica exchange molecular dynamics simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence.</div><div>The simulations were able to correctly reproduce the location of both local and non-local secondary changes due to the Val66Met mutation when compared with NMR spectroscopy. We find that the local structure change is mediated via entropic and sequence specific effects. We show that the highly disordered prodomain can be meaningfully divided into domains based on sequence alone. Monte Carlo simulations of a self-excluding heterogeneous polymer, with monomers representing each domain, suggest the sequence would be effectively segmented by the long, highly disordered polyampholyte near the sequence midpoint. This is qualitatively consistent with observed interdomain contacts within the BDNF prodomain, although contacts between the two segments are enriched relative to the self-excluding polymer. The Val66Met mutation increases interactions across the boundary between the two segments, due in part to a specific Met-Met interaction with a Methionine in the other segment. This effect propagates to cause the non-local change in secondary structure around the second methionine, previously observed in NMR. The effect is not mediated simply via changes in inter-domain contacts but is also dependent on secondary structure formation around residue 66, indicating a mechanism for secondary structure coupling in disordered proteins. </div>

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