Julien Roche

Julien Roche
Iowa State University | ISU ·  Roy J. Carver" Department of Biochemistry

Ph.D

About

44
Publications
7,293
Reads
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1,449
Citations
Citations since 2016
20 Research Items
1129 Citations
2016201720182019202020212022050100150200
2016201720182019202020212022050100150200
2016201720182019202020212022050100150200
2016201720182019202020212022050100150200
Additional affiliations
September 2012 - June 2016
The National Institute of Diabetes and Digestive and Kidney Diseases
Position
  • PostDoc Position
September 2008 - June 2012
French National Centre for Scientific Research
Position
  • PhD Student
September 2003 - June 2008
Université Montpellier 2 Sciences et Techniques
Position
  • Student

Publications

Publications (44)
Article
Full-text available
Most transcription factors possess at least one long intrinsically disordered transactivation domain that binds to a variety of co-activators and co-repressors and plays a key role in modulating the transcriptional activity. Despite the crucial importance of these domains, the structural and functional basis of transactivation remains poorly unders...
Article
Full-text available
Methanobactins (MBs) are ribosomally synthesized and post-translationally modified peptides (RiPPs) produced by methanotrophs for copper uptake. The post-translational modification that define MBs is the formation of two heterocyclic groups with associated thioamines from X-Cys dipeptide sequences. Both heterocyclic groups in the MB from Methylosin...
Article
High-pressure is a well-known perturbation method that can be used to destabilize globular proteins and dissociate protein complexes in a reversible manner. Hydrostatic pressure drives thermodynamical equilibria toward the state(s) with the lower molar volume. Increasing pressure offers, therefore, the opportunities to finely tune the stability of...
Article
Significance Enzyme I (EI) is a central player in bacterial metabolism that controls carbon uptake, virulence, and biofilm formation of bacterial cells. Conserved in gram-positive and gram-negative bacteria but absent in eukaryotes, EI is a promising target for antimicrobial design. EI’s monomer–dimer equilibrium plays a crucial role in regulating...
Article
Full-text available
We have investigated the pressure‐ and temperature‐induced conformational changes associated with the low complexity domain of hnRNP A1, an RNA‐binding protein able to phase separate in response to cellular stress. Solution NMR spectra of the hnRNP A1 low‐complexity domain fused with protein‐G B1 domain were collected from 1 to 2,500 bar and from 2...
Article
Full-text available
Disrupted-in-Schizophrenia-1 (DISC1) is a scaffold protein of significant importance for neuro-development and a prominent candidate protein in the etiology of mental disorders. In this work, we investigate the role of conformational heterogeneity and local structural disorder in the oligomerization pathway of the full-length DISC1 and of two trunc...
Article
Full-text available
The small heat-shock protein HSP27 is a redox-sensitive molecular chaperone that is expressed throughout the human body. Here, we describe redox-induced changes to the structure, dynamics, and function of HSP27 and its conserved α-crystallin domain (ACD). While HSP27 assembles into oligomers, we show that the monomers formed upon reduction are high...
Article
Full-text available
Although it is now relatively well understood how sequence defines and impacts global protein stability in specific structural contexts, the question of how sequence modulates the configurational landscape of proteins remains to be defined. Protein configurational equilibria are generally characterized by using various chemical denaturants or by ch...
Article
Full-text available
The development of computational efficient models is essential to obtain a detailed characterization of the mechanisms underlying the folding of proteins and the formation of amyloid fibrils. Structure based computational models (Go-model) with Cα or all-atom resolutions have been able to successfully delineate the mechanisms of folding of several...
Chapter
Protein conformational landscapes define their functional properties as well as their proteostasis. Hence, detailed mapping of these landscapes is necessary to understand and modulate protein conformation. The combination of high pressure and NMR provides a particularly powerful approach to characterizing protein conformational transitions. First,...
Article
Full-text available
Using fine-tuned hydrogen bonding criteria, a library of coiled peptide fragments has been generated from a large set of high-resolution protein X-ray structures. This library is shown to be an improved representation of ϕ/ψ torsion angles seen in intrinsically disordered proteins (IDPs). The ϕ/ψ torsion angle distribution of the library, on averag...
Article
High-pressure is a well-known perturbation method used to destabilize globular proteins. It is perfectly reversible, which is essential for a proper thermodynamic characterization of a protein equilibrium. In contrast to other perturbation methods such as heat or chemical denaturant that destabilize protein structures uniformly, pressure exerts loc...
Article
High-pressure is a well-known perturbation method used to destabilize globular proteins and dissociate protein complexes or aggregates. The heterogeneity of the response to pressure offers a unique opportunity to dissect the thermodynamic contributions to protein stability. In addition, pressure perturbation is generally reversible, which is essent...
Article
Full-text available
We report structural analysis of HIV protease variant PRS17 which was rationally selected by machine learning to represent wide classes of highly drug-resistant variants. Crystal structures were solved of PRS17 in the inhibitor-free form and in complex with antiviral inhibitor, darunavir. Despite its 17 mutations, PRS17 has only one mutation (V82S)...
Article
Full-text available
The transitioning of the ectodomain of gp41 from a pre-hairpin to a six-helix bundle conformation is a crucial aspect of virus-cell fusion. To gain insight into the intermediary steps of the fusion process we have studied the pH and dodecyl phosphocholine (DPC) micelle dependent trimer association of gp41 by systematic deletion analysis of an optim...
Article
Full-text available
A new and convenient method, named ARTSY-J, is introduced that permits extraction of the 3JHNHα couplings in proteins from the relative intensities in a pair of 15N-1H TROSY-HSQC spectra. The pulse scheme includes 3JHNHα dephasing of the narrower TROSY 1HN-{15N} doublet component during a delay, integrated into the regular two-dimensional TROSY-HSQ...
Article
Full-text available
Using high-pressure NMR spectroscopy and differential scanning calorimetry, we investigate the folding landscape of the mature HIV-1 protease homodimer. The cooperativity of unfolding was measured in the absence or presence of an active site inhibitor DMP323, for the active protease (PR), its inactive variant PRD25N and an extremely multi-drug resi...
Article
Full-text available
The pathogenesis of Alzheimer's disease is characterized by the aggregation and fibrillation of the amyloid peptides Aβ1-40 and Aβ1-42 into amyloid plaques. Despite strong potential therapeutic interest, the structural pathways associated with the conversion of monomeric Aβ peptides into oligomeric species remain largely unknown. In particular, the...
Article
Full-text available
Provided that care is taken in adjusting the WATERGATE element of a (1)H-(15)N TROSY-HSQC experiment, such that neither the water magnetization nor the (1)H(α) protons are inverted by its final 180° pulse, (3)JHNHα couplings can be measured directly from splittings in the (1)H dimension of the spectrum. With band-selective (1)H decoupling, very hig...
Article
Full-text available
We investigate the pressure-induced structural changes in the mature human immunodeficiency virus type 1 protease dimer (HIV-1 PR), using residual dipolar coupling (RDC) measurements in a weakly oriented solution. (1) DNH RDCs were measured under high-pressure conditions for an inhibitor-free PR and an inhibitor-bound complex, as well as for an inh...
Article
The energetic and volumetric properties of a three-state protein folding system, comprising a metastable triple mutant of the Fyn SH3 domain, have been investigated using pressure-dependent 15N-relaxation dispersion NMR from 1 to 2500 bar. Changes in partial molar volumes (ΔV) and isothermal compressibilities (ΔκT) between all the states along the...
Article
The energetic and volumetric properties of a three-state protein folding system, comprising a metastable triple mutant of the Fyn SH3 domain, have been investigated using pressure-dependent 15N-relaxation dispersion NMR from 1 to 2500 bar. Changes in partial molar volumes (ΔV) and isothermal compressibilities (ΔκT) between all the states along the...
Article
Full-text available
Defining the physical-chemical determinants of protein folding and stability, under normal and pathological conditions has constituted a major subfield in biophysical chemistry for over 50 years. Although a great deal of progress has been made in recent years towards this goal, a number of important questions remain. These include characterizing th...
Article
The way in which the network of intramolecular interactions determines the cooperative folding and conformational dynamics of a protein remains poorly understood. High pressure NMR spectroscopy is uniquely suited to examine this problem because it combines the site-specific resolution of the NMR experiments with the local character of pressure pert...
Article
Full-text available
The envelope glycoprotein gp41 mediates the process of membrane fusion that enables entry of the HIV-1 virus into the host cell. Strong lipid affinity of the ecto-domain suggests that its heptad repeat regions play an active role in destabilizing membranes by directly binding to the lipid bilayers and thereby lowering the free-energy barrier for me...
Article
Full-text available
The flexibility of the glycine-rich flaps are known to be essential for the catalytic activity of the HIV-1 Protease but their exact conformations at the different stages of the enzymatic pathway remain yet to be determined. While hundreds of crystal structures of protease-inhibitor complexes have been solved, only a dozen of unbound protease struc...
Article
Full-text available
Flexibility of the glycine-rich flaps is known to be essential for catalytic activity of the HIV-1 protease, but their exact conformations at the different stages of the enzymatic pathway remain subject to much debate. Although hundreds of crystal structures of protease–inhibitor complexes have been solved, only about a dozen inhibitor-free proteas...
Article
Full-text available
We previously reported a series of antibodies, in fragment antigen binding domain (Fab) formats, selected from a human non-immune phage library, directed against the internal trimeric coiled-coil of the N-heptad repeat (N-HR) of HIV-1 gp41. Broadly neutralizing antibodies from that series bind to both the fully exposed N-HR trimer, representing the...
Article
Full-text available
The antibiotic squalamine, originally isolated from dogfish shark, forms a lyotropic liquid crystal at very low concentrations in water (0.3-3.5% w/v), which remains stable over a wide range of temperature (1-40 °C) and pH (4-8). Squalamine is positively charged, and comparison of the alignment of ubiquitin relative to 36 previously reported alignm...
Article
Full-text available
Significance Infection by HIV-1 requires fusion of viral and host cell membranes, a process mediated by viral protein gp41. Although extensive structural detail on both pre- and postfusion gp41 states is available from X-ray crystallography and cryo-EM studies, little is known about the actual transition. This NMR study of a trimeric gp41 ectodomai...
Article
During treatment, mutations in HIV-1 protease (PR) are selected rapidly that confer resistance by decreasing affinity to clinical protease inhibitors (PIs). As these unique drug resistance mutations can compromise the fitness of the virus to replicate, mutations that restore conformational stability and activity while retaining drug resistance are...
Article
Full-text available
The impact of pressure on the backbone (15) N, (1) H and (13) C chemical shifts in N-terminally acetylated α-synuclein has been evaluated over a pressure range 1-2500 bar. Even while the chemical shifts fall very close to random coil values, as expected for an intrinsically disordered protein, substantial deviations in the pressure dependence of th...
Article
The time required to fold proteins usually increases significantly under conditions of high pressure. Taking advantage of this general property of proteins, we combined P-jump experiments with NMR spectroscopy to examine in detail the folding reaction of staphylococcal nuclease (SNase) and of some of its cavity-containing variants. The nearly 100 o...
Article
The effects of cavity-creating mutations on the structural flexibility, local and global stability and dynamics of the folded state of staphylococcal nuclease (SNase) were examined with NMR spectroscopy, MD simulations, H/D exchange and pressure perturbation. Effects on global thermodynamic stability correlated well with the number of heavy atoms i...
Article
The magnitude and sign of the volume change upon protein unfolding are strongly dependent on temperature. This temperature dependence reflects differences in the thermal expansivity of the folded and unfolded states. The factors that determine protein molar expansivities and the large differences in thermal expansivity for proteins of similar molar...
Article
Full-text available
The folding of staphylococcal nuclease (SNase) is known to proceed via a major intermediate in which the central OB sub-domain is folded and the C-terminal helical sub-domain is disordered. To identify the structural and energetic determinants of this folding free energy landscape we have examined in detail, using high pressure NMR, the consequence...
Article
Full-text available
It has been known for nearly 100 years that pressure unfolds proteins, yet the physical basis of this effect is not understood. Unfolding by pressure implies that the molar volume of the unfolded state of a protein is smaller than that of the folded state. This decrease in volume has been proposed to arise from differences between the density of bu...
Article
The ionization of internal groups in proteins can trigger conformational change. Despite this being the structural basis of most biological energy transduction, these processes are poorly understood. Small angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy experiments at ambient and high hydrostatic pressure were used t...
Article
The application of hydrostatic pressure generally leads to protein unfolding, implying, in accordance with Le Chatelier's principle, that the unfolded state has a smaller molar volume than the folded state. However, the origin of the volume change upon unfolding, ΔV(u), has yet to be determined. We have examined systematically the effects of protei...
Article
Spectral density mapping at multiple NMR field strengths is probably the best method to describe the dynamics behavior of a protein in solution through the analysis of 15N heteronuclear relaxation parameters. Nevertheless, such analysis is scarcely reported in the literature, probably because this method is excessively demanding in spectrometer mea...

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Project (1)
Project
We explore the biochemical and structural mechanisms by which DISC1 regulates the cAMP signalization pathway