SUMO's Intrinsically Disordered N-Terminus is an Intramolecular Inhibitor of SUMO - SIM Interactions

2020 ◽  
Author(s):  
Sebastian M. Richter ◽  
Fan Jin ◽  
Eric Maurer ◽  
Annette Flotho ◽  
Frauke Gräter ◽  
...  
Keyword(s):  
Intrinsically Disordered ◽  
N Terminus

scholarly journals Clustering of human prion protein and α-synuclein oligomers requires the prion protein N-terminus

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Nadine S. Rösener ◽  
Lothar Gremer ◽  
Michael M. Wördehoff ◽  
Tatsiana Kupreichyk ◽  
Manuel Etzkorn ◽  
...  
Keyword(s):  
Prion Protein ◽  
Amyloid Β ◽  
Intrinsically Disordered Protein ◽  
Molar Ratio ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
N Terminus ◽  
Human Prion Protein ◽  
Intrinsically Disordered Protein Region ◽  
Slow Dissociation

AbstractThe interaction of prion protein (PrP) and α-synuclein (αSyn) oligomers causes synaptic impairment that might trigger Parkinson’s disease and other synucleinopathies. Here, we report that αSyn oligomers (αSynO) cluster with human PrP (huPrP) into micron-sized condensates. Multivalency of αSyn within oligomers is required for condensation, since clustering with huPrP is not observed for monomeric αSyn. The stoichiometry of the heteroassemblies is well defined with an αSyn:huPrP molar ratio of about 1:1. The αSynO−huPrP interaction is of high affinity, signified by slow dissociation. The huPrP region responsible for condensation of αSynO, residues 95−111 in the intrinsically disordered N-terminus, corresponds to the region required for αSynO-mediated cognitive impairment. HuPrP, moreover, achieves co-clustering of αSynO and Alzheimer’s disease-associated amyloid-β oligomers, providing a case of a cross-interaction of two amyloidogenic proteins through an interlinking intrinsically disordered protein region. The results suggest that αSynO-mediated condensation of huPrP is involved in the pathogenesis of synucleinopathies.

scholarly journals The N-Terminus of the Intrinsically Disordered Protein α-Synuclein Triggers Membrane Binding and Helix Folding

2010 ◽  
Vol 99 (7) ◽  
pp. 2116-2124 ◽  
Author(s):  
Tim Bartels ◽  
Logan S. Ahlstrom ◽  
Avigdor Leftin ◽  
Frits Kamp ◽  
Christian Haass ◽  
...  
Keyword(s):  
Membrane Binding ◽  
Intrinsically Disordered Protein ◽  
Intrinsically Disordered ◽  
Disordered Protein ◽  
N Terminus

scholarly journals Extent of N-terminus exposure by altered long-range interactions of monomeric alpha-synuclein determines its aggregation propensity

2019 ◽  
Author(s):  
Amberley D. Stephens ◽  
Maria Zacharopoulou ◽  
Rani Moons ◽  
Giuliana Fusco ◽  
Neeleema Seetaloo ◽  
...  
Keyword(s):  
Long Range ◽  
Intrinsically Disordered Protein ◽  
Local Environment ◽  
Alpha Synuclein ◽  
Conformational Space ◽  
Conformational Ensemble ◽  
Aggregation Propensity ◽  
Intrinsically Disordered ◽  
Long Range Interactions ◽  
N Terminus

AbstractAs an intrinsically disordered protein, monomeric alpha synuclein (aSyn) constantly reconfigures and probes the conformational space. Long-range interactions across the protein maintain its solubility and mediate this dynamic flexibility, but also provide residual structure. Certain conformations lead to aggregation prone and non-aggregation prone intermediates, but identifying these within the dynamic ensemble of monomeric conformations is difficult. Herein, we used the biologically relevant calcium ion to investigate the conformation of monomeric aSyn in relation to its aggregation propensity. By using calcium to perturb the conformational ensemble, we observe differences in structure and intra-molecular dynamics between two aSyn C-terminal variants, D121A and pS129, and the aSyn familial disease mutants, A30P, E46K, H50Q, G51D, A53T and A53E, compared to wild-type (WT) aSyn. We observe that the more exposed the N-terminus and the beginning of the NAC region are, the more aggregation prone monomeric aSyn conformations become. N-terminus exposure occurs upon release of C-terminus interactions when calcium binds, but the level of exposure is specific to the aSyn mutation present. There was no correlation between single charge alterations, calcium affinity, or the number of ions bound on aSyn’s aggregation propensity, indicating that sequence or post-translation modification (PTM)-specific conformational differences between the N- and C-termini and the specific local environment mediate aggregation propensity instead. Understanding aggregation prone conformations of monomeric aSyn and the environmental conditions they form under will allow us to design new therapeutics targeted to the monomeric protein, to stabilise aSyn in non-aggregation prone conformations, by either preserving long-range interactions between the N- and C-termini or by protecting the N-terminus from exposure.

scholarly journals Structural Determinants of the Prion Protein N-Terminus and Its Adducts with Copper Ions

2018 ◽  
Vol 20 (1) ◽  
pp. 18 ◽  
Author(s):  
Carolina Sánchez-López ◽  
Giulia Rossetti ◽  
Liliana Quintanar ◽  
Paolo Carloni
Keyword(s):  
Prion Protein ◽  
Copper Ions ◽  
Proteolytic Processing ◽  
Copper Binding ◽  
Structural Determinants ◽  
Intrinsically Disordered ◽  
Structural And Functional Properties ◽  
N Terminus ◽  
Functional Implications ◽  
Health And Disease

The N-terminus of the prion protein is a large intrinsically disordered region encompassing approximately 125 amino acids. In this paper, we review its structural and functional properties, with a particular emphasis on its binding to copper ions. The latter is exploited by the region’s conformational flexibility to yield a variety of biological functions. Disease-linked mutations and proteolytic processing of the protein can impact its copper-binding properties, with important structural and functional implications, both in health and disease progression.

scholarly journals The spliceosomal proteins PPIH and PRPF4 exhibit bi-partite binding

2017 ◽  
Vol 474 (21) ◽  
pp. 3689-3704 ◽  
Author(s):  
Caroline Rajiv ◽  
S. RaElle Jackson ◽  
Simon Cocklin ◽  
Elan Z. Eisenmesser ◽  
Tara L. Davis
Keyword(s):  
Protein Interactions ◽  
Protein Complex ◽  
Mutational Analysis ◽  
Core Protein ◽  
Point Mutations ◽  
Unexpected Result ◽  
Small Nuclear Rna ◽  
Peptidyl Prolyl Isomerase ◽  
Intrinsically Disordered ◽  
N Terminus

Pre-mRNA splicing is a dynamic, multistep process that is catalyzed by the RNA (ribonucleic acid)–protein complex called the spliceosome. The spliceosome contains a core set of RNAs and proteins that are conserved in all organisms that perform splicing. In higher organisms, peptidyl-prolyl isomerase H (PPIH) directly interacts with the core protein pre-mRNA processing factor 4 (PRPF4) and both integrate into the pre-catalytic spliceosome as part of the tri-snRNP (small nuclear RNA–protein complex) subcomplex. As a first step to understand the protein interactions that dictate PPIH and PRPF4 function, we expressed and purified soluble forms of each protein and formed a complex between them. We found two sites of interaction between PPIH and the N-terminus of PRPF4, an unexpected result. The N-terminus of PRPF4 is an intrinsically disordered region and does not adopt secondary structure in the presence of PPIH. In the absence of an atomic resolution structure, we used mutational analysis to identify point mutations that uncouple these two binding sites and find that mutations in both sites are necessary to break up the complex. A discussion of how this bipartite interaction between PPIH and PRPF4 may modulate spliceosomal function is included.

scholarly journals The Disordered C-Terminus of the Chaperone DnaK Increases the Competitive Fitness of Pseudomonas putida and Facilitates the Toxicity of GraT

2021 ◽  
Vol 9 (2) ◽  
pp. 375
Author(s):  
Sirli Rosendahl ◽  
Andres Ainelo ◽  
Rita Hõrak
Keyword(s):  
Quality Control ◽  
Protein Folding ◽  
Pseudomonas Putida ◽  
Optimal Growth ◽  
Competitive Fitness ◽  
Growth Defects ◽  
Intrinsically Disordered ◽  
C Terminus ◽  
Chaperone Dnak ◽  
N Terminus

Chaperone proteins are crucial for proper protein folding and quality control, especially when cells encounter stress caused by non-optimal temperatures. DnaK is one of such essential chaperones in bacteria. Although DnaK has been well characterized, the function of its intrinsically disordered C-terminus has remained enigmatic as the deletion of this region has been shown to either enhance or reduce its protein folding ability. We have shown previously that DnaK interacts with toxin GraT of the GraTA toxin-antitoxin system in Pseudomonas putida. Interestingly, the C-terminal truncation of DnaK was shown to alleviate GraT-caused growth defects. Here, we aim to clarify the importance of DnaK in GraT activity. We show that DnaK increases GraT toxicity, and particularly important is the negatively charged motif in the DnaK C-terminus. Given that GraT has an intrinsically disordered N-terminus, the assistance of DnaK is probably needed for re-modelling the toxin structure. We also demonstrate that the DnaK C-terminal negatively charged motif contributes to the competitive fitness of P. putida at both high and optimal growth temperatures. Thus, our data suggest that the disordered C-terminal end of DnaK enhances the chaperone functionality.

scholarly journals The intrinsically disordered N-terminus of the voltage-dependent anion channel

2021 ◽  
Vol 17 (2) ◽  
pp. e1008750
Author(s):  
Jordane Preto ◽  
Isabelle Krimm
Keyword(s):  
Force Field ◽  
Disordered Systems ◽  
Anion Channel ◽  
Dynamics Simulation ◽  
Mitochondrial Outer Membrane ◽  
Voltage Dependent Anion Channel ◽  
Intrinsically Disordered ◽  
Gating Mechanism ◽  
N Terminus ◽  
Voltage Dependent

The voltage-dependent anion channel (VDAC) is a critical β-barrel membrane protein of the mitochondrial outer membrane, which regulates the transport of ions and ATP between mitochondria and the cytoplasm. In addition, VDAC plays a central role in the control of apoptosis and is therefore of great interest in both cancer and neurodegenerative diseases. Although not fully understood, it is presumed that the gating mechanism of VDAC is governed by its N-terminal region which, in the open state of the channel, exhibits an α-helical structure positioned midway inside the pore and strongly interacting with the β-barrel wall. In the present work, we performed molecular simulations with a recently developed force field for disordered systems to shed new light on known experimental results, showing that the N-terminus of VDAC is an intrinsically disordered region (IDR). First, simulation of the N-terminal segment as a free peptide highlighted its disordered nature and the importance of using an IDR-specific force field to properly sample its conformational landscape. Secondly, accelerated dynamics simulation of a double cysteine VDAC mutant under applied voltage revealed metastable low conducting states of the channel representative of closed states observed experimentally. Related structures were characterized by partial unfolding and rearrangement of the N-terminal tail, that led to steric hindrance of the pore. Our results indicate that the disordered properties of the N-terminus are crucial to properly account for the gating mechanism of VDAC.

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