Amyloidogenesis of proteolytic fragments of human elastin

Some polypeptides encoded by the C-terminal region of human tropoelastin gene have been demonstrated to be amyloidogenic in vitro. The biological relevance of this finding is still under investigation given that only limited evidence concerning the involvement of elastin in amyloidosis exists. Recent studies identified, by mass spectrometry, several elastin fragments produced from the cleavages made by some elastases in human elastin substrate. Some of these fragments are contained into the same polypeptide sequences previously demonstrated to be amyloidogenic. Our hypothesis is that the upregulation of elastases in inflammatory processes triggered, for example, by aging induces the release of elastin fragments potentially amyloidogenic. Therefore our aim in this study is to demonstrate if any of these fragments is amyloidogenic in vitro. At molecular level, CD, NMR, FTIR spectroscopies and MD simulations were used, while, at supramolecular level, Congo red binding assay and ThT fluorescence spectroscopy complemented with AFM microscopy were carried out. Our results show that the longest peptide, among those synthesized and mimicking the elastin fragments produced by elastases on human elastin, constituted of 22 residues, is able to aggregate into amyloid-like fibres. These findings support the hypothesis of amyloidogenesis of proteolytic fragments of elastin

Logistik: Hur påverkar Just-In-Time på lönsamheten av ett företag?

Ett företag har som grunduppgift att hållas verksamt genom att ekonomiskt prestera bättre för varje år. Logistik är det verksamhetsområde som står för majoriteten av ett företags kostnader. Kostnader i sig är en dålig sak för företag, men det är även en möjlighet för logistiken att sänka dessa kostnader, vilket i sin tur är bra för företagets lön-samhet. Just-In-Time (JIT) är en produktions- och styrfilosofi inom logistiken, där det huvudsakliga målet är att minska lagernivåerna och att eliminera allt onödigt. Syftet med denna studie är att finna ett samband mellan JIT och lönsamhet ur ett logistiskt perspektiv. Vid studien används DuPont-modellen som definition av lönsamhet samt som ett jämförelseverktyg där sex olika finansiella faktorer mäts. Metoden för studien är kvalitativ i form av en litteraturstudie. Materialet som analyseras hämtas endast från Arcadas databaser och analysen av materialet sker i form av innehållsanalys. Resultaten av materialet som analyserades är väldigt blandat. Många studier påpekar att det råder brist på forskning inom detta ämnesområdet, vilket även kan vara orsaken till dessa blandade resultat. Det går dock att urskilja tre finansiella mått från DuPont-modellen som påver-kas positivt av JIT. Dessa är: intäkter, kostnader och lager. Ingen studie visade att JIT skulle ha negativ inverkan på ett företags lönsamhet. Andra intressanta faktorer som JIT hade en positiv inverkan på är operativa prestanda, t.ex. minskade ledtider

Low-diluted Phenacetinum disrupted the melanoma cancer cell migration

Dynamic and reciprocal interactions generated by the communication between tumor cells and their matrix microenvironment, play a major role in the progression of a tumor. Indeed, the adhesion of specific sites to matrix components, associated with the repeated and coordinated formation of membrane protrusions, allow tumor cells to move along a determined pathway. Our study analyzed the mechanism of action of low-diluted Phenacetinum on murine cutaneous melanoma process in a fibronectin matrix environment. We demonstrated a reduction of dispersed cell migration, early and for as long as 24 h, by altering the formation of cell protrusions. Moreover, low-diluted Phenacetinum decreased cell stiffness highly on peripheral areas, due to a disruption of actin filaments located just under the plasma membrane. Finally, it modified the structure of the plasma membrane by accumulating large ordered lipid domains and disrupted B16 cell migration by a likely shift in the balance between ordered and disordered lipid phases. Whereas the correlation between the excess of lipid raft and cytoskeleton disrupting is not as yet established, it is clear that low-diluted Phenacetinum acts on the actin cytoskeleton organization, as confirmed by a decrease of cell stiffness affecting ultimately the establishment of an effective migration process

Elaboration d'une base de parametres de la fonction energie potentielle empirique de saccharides en vue de son utilisation en mecanique moleculaire et dynamique moleculaire de glycannes

SIGLEINIST T 73908 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

A critical disulfide bridge in elastins. Modeling from spectroscopic data to 3D structures.

International audienc

Simulation par dynamique moléculaire de membranes lipidiques complexes

REGI

Privileged hydration sites in aromatic side chains: effect on conformational equilibrium

International audienc

Etude de peptides amyloïdogéniques dérivés de la tropoélastine humaine par simulations numériques

Ce travail de thèse porte sur l étude de peptides dérivés de la tropoélastine par simulations de dynamique moléculaire en solvant explicite. Ces peptides sont issus des exons 7, 28 et 30 et possèdent une séquence consensus XGGZG (X, Z = Valine, Leucine) identifiée expérimentalement comme responsable de la formation d assemblages supramoléculaire ayant des propriétés amyloïdes. Nous montrons tout d abord que le motif minimal XGGZG et (XGGZG) adoptent un grand nombre de coudes quel que soit la permutation entre valine et leucine et que localement les résidus non glycine présentent une conformation de type polyproline II dans des proportions significatives. L étude des répétitions (XGGZG)3 fait apparaître des structures allant du feuillet b antiparallèle pour (VGGVG)3 à de l hélice a et 310 pour (LGGLG)3. Les répétitions (VGGLG) 3 et (LGGVG)3 donnent pour leur part à la fois des structures comportant de faibles proportions d hélices ou de feuillets. Des résultats équivalents sont obtenus sur les exons 28 et 30 entiers, ainsi que sur le peptide comprenant les 17 premier résidus de l exon 30. La création d un plancher poly(VGGVG) de brins b virtuellement infini nous permet de montrer qu en sa présence, des peptides VGGVG peuvent s organiser parallèlement ou perpendiculairement à ce dernier. Enfin, es simulations préliminaires distinctes ont été menées afin d évaluer le rôle du cholestérol dans les phénomènes d agrégation ou dynamiques des peptides dérivés de la tropélastine. Des études de l effet biologique des peptides ont été débutées et sont une perspectives intéressantes de ce travail.This work deals with the study of tropoelastin-derived peptides by molecular dynamics simulations in explicit solvent. These peptides are identified in exons 7, 28 and 30 possess a consensus sequence XGGZG (X, Z = Valine, Leucine) described experimentally as responsible for the formation of supramolecular assemblies with amyloid properties. We first show that the minimal motif XGGZG and (XGGZG) adopt a large number of turns, independently of the permutation of valine and leucine residues. Locally, non-glycine residues exhibit polyproline-II conformation in significant proportions. The study of (XGGZG)3 show that it gives rise to structure form antiparallel b sheets for (VGGVG)3 to a and 310 helices for (LGGLG)3. (VGGLG)3 and (LGGVG)3 sequences give rise to both structures in small proportions. Equivalent results are obtained on the entire exons 28 and 30, and the peptide including the first 17 residues of exon 30. The construction of a poly(VGGVG) plan with virtually infinite b strand allows us to show that in contact with it, VGGVG peptides can organize parallel or perpendicularly to the plan. Finally, separate preliminary simulations were conducted to evaluate the role of cholesterol in the phenomena of aggregation and dynamics to tropoelastin-derived peptides. Studies of the biological effect of these peptides were initiated and are an interesting perspective of this work.REIMS-BU Sciences (514542101) / SudocSudocFranceF

Human thrombospondin’s (TSP-1) C-terminal domain opens to interact with the CD-47 receptor: A molecular modeling study

International audienceThrombospondin-1 (TSP-1) interaction with the membranous receptor CD-47 involves the peptide RFYVVMWK (4N-1) located in its C-terminal domain. However, the available X-ray structure of TSP-1 describes this peptide as completely buried into a hydrophobic pocket, preventing any interaction. Where classical standard methods failed, an appropriate approach combining normal mode analysis and an adapted protocol of energy minimization identified the large amplitude motions responsible of the partial solvent exposure of 4N-1. In agreement, the obtained model of the open TSP-1 was further used for protein-protein docking experiments against a homology model generated for CD-47. Considering the multiple applications of the CD-47 receptor as a target, our results open new pharmacological perspectives for the design of TSP-1:CD-47 inhibitors and CD-47 antagonists. We also suggest a common opening mechanism for proteins sharing the same fold as TSP-1. This work also suggests the usefulness of our approach in other topics in which predictions of protein-protein interactions are of importance

Mesoscopic Rigid Body Modelling of the Extracellular Matrix Self-Assembly

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