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Acquasaliente, Laura (2014) Coagulation protein factors: discovering novel interactions of thrombin. [Tesi di dottorato]

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Abstract (inglese)

Thrombin is a serine protease of the chymotrypsin family. Compared to chymotrypsin, thrombin displays several insertion loops, responsible for the unique substrate specificity of the enzyme. Two different insertions shape and narrow the access to the active site, while the interaction of binders involves allosteric sites, called exosite-I (Anion Binding Exosite-I or Fibrinogen Recognition Site) and exosite-II (Anion Binding Exosite-II or Heparin Binding Site). These contain electropositive amino acid residues and are localized at opposite poles of the active site, representing two potential exosites for the binding of macromolecular ligands. Exosite-I is involved in binding to fibrinogen, platelet receptor PAR-1, thrombomodulin, and to endogenous (i.e. heparin cofactor II) and exogenous (i.e. C-terminal tail of hirudin) inhibitors. Exosite-II interacts with heparin, F2 prothrombin fragment, and physiological inhibitors such us antithrombin III and protease nexin-I. Contrary to chymotrypsin, the proteolytic activity of thrombin is enhanced upon binding of Na+, that stabilizes the enzyme into a more open and rigid conformation.
Thrombin is a multifunctional enzyme that plays a key role at interface between coagulation, inflammation and nervous system. The protease is involved in numerous physiological and pathological processes, including haemostasis and thrombosis, inflammation and chemotaxis, cellular proliferation and tumor growth, angiogenesis and neurodegenerative diseases, manifesting pleiotropic effects. For example, low concentrations of thrombin (i.e. 1-10nM) can influence glia cell mitosis and neuronal out-growth, acts as mitogen. Conversely, higher concentration of the enzyme (100nM) has been shown to induce apoptosis in motor neurons and to determine in the brain a pro-inflammatory state. Instead, in vivo, the dynamic concentration of free thrombin during coagulation cascade reactions is estimated to vary from 1nM to over 100 – 500nM. Typically low concentration are associated with platelet activation and loosely organised fibrin strands susceptible to fibrinolysis; higher concentration produce tightly packet fibrin strands capable of forming a stable clot. Some of these effects are mediated by activation of Protease Activated Receptors (PARs). The general mechanism by which proteases activate PARs is the same: enzymes cleave at specific sites within the extracellular amino terminus of the receptors; this cleavage exposes a new amino terminus that serves as a tethered ligand domain, which binds to conserved regions in the second extracellular loop of the cleaved receptor, resulting in the initiation of signal transduction. All these observations argue in favor of a biochemical communication between the different mechanisms regulating the cellular effects of thrombin.
The general aim of my PhD project was to identify novel effectors of thrombin, whose interaction may have important implications in defining the biochemical processes that regulate the onset and progression of cardiovascular diseases, neurodegenerative and autoimmune diseases.
During the first year, I studied the effect of beta2-glycoprotein I (b2GPI) on the procoagulant (i.e. fibrin generation and platelet aggregation) and anticoagulant (i.e. generation of activated protein C) functions of thrombin (Chapter 2). b2GPI, identified as the major antigen of antiphospholipid syndrome (APS), functions as a physiologic anticoagulant by inhibiting the key procoagulant activities of the protease, without affecting its unique anticoagulant function. Our experiments, conducted by surface plasmon resonance (SPR), clarify the binding mode of interaction: b2GPI binds to thrombin exosites, while the active site remains free and accessible for substrate binding.
In the second year of my PhD course, I have investigated the interaction between alpha-synuclein (a-Syn) and human thrombin (Chapter 3). a-Syn is a small soluble presynaptic protein implicated in different neurodegenerative disorders. Recent studies indicated that a-Syn is able to inhibit platelets degranulation, upon thrombin stimulation. In addition, clinical studies indicated that the incidence of ischemic stroke in patients with Parkinson disease is lower than in controls, and platelet aggregation is also significantly decreased. Our results suggest that the acidic C-terminal portion of -Syn binds to thrombin exosites (Kd ~ uM). Consequently, we speculate that the complex [a-Syn – thrombin] effectively hinders platelet aggregation, due to the interaction of the N-terminal domain on the platelets surfaces.
During the last year, I studied human ceruloplasmin (CP) as a possible binder of thrombin (Chapter 4). The plasma level of CP is an important diagnostic indicator of inflammatory disease, such as Rheumatoid Arthritis (RA), a chronic systemic inflammatory autoimmune disorder. As observed with CP, thrombin concentration is markedly increased in inflamed tissues and specifically in the synovial fluid of RA patients. We conclude that the anti-inflammatory function of CP is regulated by thrombin: the enzyme, in fact, proteolytically hinders the antioxidant activity of CP. These results are confirmed in RA patients treated with hirudin that have clinical symptoms ameliorated. These data are unprecedented and set the basis for elucidating the biochemical mechanisms underlying the progression of inflammation in RA patients.

Abstract (italiano)

La trombina è una proteasi serinica appartenente, per omologia di sequenza, alla famiglia della chimotripsina dalla quale differisce per la presenza di numerosi loop d’inserzione, che le conferiscono una peculiare specificità di substrato. Essa si presenta come un ellissoide caratterizzato da due beta-barrels, alla giunzione dei quali si colloca la cavità che ospita il sito attivo. Il riconoscimento molecolare dei diversi effettori, invece, è mediato da due regioni superficiali elettropositive, diametralmente opposte e circondanti la cavità catalitica. Queste sono definite, rispettivamente, esosito-I (Anion Binding Exosite-I o Fibrinogen Recognition Site) ed esosito-II (Anion Binding Exosite-II o Heparin Binding Site). L’esosito-I è coinvolto nel legame della trombina al fibrinogeno, al recettore piastrinico PAR-1, alla trombomodulina, e a inibitori endogeni, come il fattore eparinico II, ed esogeni come la coda C-terminale dell’irudina. L’esosito-II rappresenta il sito di legame per l’eparina, per il frammento F2 della pro-trombina e per inibitori fisiologici come l’antitrombina III e la nexina-I. A differenza della chimotrispsina, l’attività proteolitica della trombina è aumentata dal binding del Na+ che stabilizza l’enzima in una conformazione più aperta e rigida.
La trombina è una proteasi multifunzionale: da una parte gioca un ruolo importante nella cascata coagulativa, dall’altra interviene in modo fondamentale nei processi infiammatori a carico del sistema nervoso centrale. Infatti, la trombina svolge un ruolo chiave all’interfaccia tra coagulazione, infiammazione, differenziamento cellulare, angiogenesi e malattie neurodegenartive, manifestando così effetti pleiotropici. Studi in vitro hanno evidenziato come tale proteina sia in grado di modulare la permeabilità vascolare, la formazione di neo-vasi e la ritrazione di neuriti su cellule di neuroblastoma; per di più sembra svolgere attività mitogena a carico di cellule muscolari ed endoteliali. Questi effetti si realizzano a basse concentrazioni (1-10nM), mentre concentrazioni maggiori (100nM) sembrano essere nocive e pro-infiammatorie a livello cerebrale. Allo stesso modo, elevate concentrazioni plasmatiche di trombina (100-500nM) portano alla formazione di un clot compatto di fibrina, non suscettibile a fibrinolisi. Alcuni studi hanno dimostrato come la maggior parte delle funzioni non emostatiche si manifestino mediante l’attivazione dei recettori piastrinici PAR (Protease Activated Receptors), recettori transmembrana accoppiati a proteine-G. Nel dettaglio, il dominio extracellulare del PAR-1, in seguito a proteolisi promossa dalla trombina, interagisce col corpo recettoriale favorendo la trasduzione del segnale all’interno di piastrine e macrofagi. Il tutto si traduce in una risposta pro-aggregante e pro-infiammatoria. Questi dati suggeriscono la presenza di una stretta comunicazione biochimica tra i vari meccanismi che regolano i differenti effetti cellulari della trombina.
Alla luce di queste considerazioni, l’obiettivo saliente del mio Progetto di Dottorato è stato quello di identificare nuovi effettori della trombina, i cui meccanismi di interazione possono avere importanti ricadute nella definizione dei processi biochimici che regolano l’insorgenza e la progressione delle malattie cardiovascolari, neurodegenerative ed autoimmuni.
Durante il primo anno ho studiato l’effetto della beta2 glicoproteina I (b2GpI) sulle funzioni pro- e anti- coagulanti della trombina (Capitolo 2). La b2GpI, identificata come il principale antigene della sindrome da anticorpi antifosfolipidi (APS), è in grado di inibire le attività procoagulanti (generazione di fibrina ed aggregazione piastrinica) della trombina in vitro, senza compromettere l’unica sua funzione anticoagulante, ovvero la generazione di Proteina C attiva. I nostri esperimenti, condotti principalmente mediante surface plasmon resonance (SPR) hanno permesso inoltre di chiarire il binding mode di interazione delle due proteine: la b2GpI si lega agli esositi della trombina, il cui sito attivo rimane quindi accessibile al substrato.
Nel corso del secondo anno ho indagato l’interazione tra l’alpha-sinucleina (a-Sin) e la trombina umana (Capitolo 3). a-Sin è una piccola proteina solubile presinaptica, implicata in diverse patologie neurodegenerative. Recentemente è stato dimostrato come l’a-Sin sia in grado di inibire l’attivazione e quindi l’aggregazione delle piastrine quando stimolate da trombina, limitando il rilascio degli alpha-granuli. Inoltre pazienti affetti dal morbo di Parkinson sono meno soggetti ad attacchi ischemici e presentano una velocità di aggregazione piastrinica significativamente ridotta. I risultati da noi ottenuti indicano che la porzione acida C-terminale dell’a-Sin è in grado di legarsi alla trombina con un’affinità nell’ordine del basso micromolare, coinvolgendo i due esositi. Quindi, il complesso [a-Sin - trombina] ostacola efficacemente l’aggregazione piastrinica, molto probabilmente in seguito all’ancoraggio del dominio N-terminale sulla superficie delle piastrine.
Infine, durante l’ultimo anno, è stata presa in considerazione la ceruloplasmina umana (CP), quale possibile binder della trombina (Capitolo 4). Elevati livelli di CP sono stati individuati in pazienti affetti da artrite reumatoide, malattia infiammatoria cronica autoimmunitaria a carico delle articolazioni sinoviali. Come osservato per la CP, i livelli di trombina sono notevolmente aumentati in tessuti infiammati e, in modo particolare, nel fluido sinoviale di pazienti affetti da artrite reumatoide. Difatti, la trombina agisce come mediatore pro-infiammatorio e chemiotattico. In nostri dati indicano che la trombina è in grado di ostacolare, in seguito a proteolisi, l’attività antiossidante della ceruloplasmina. Queste evidenze sperimentali sono state confermate dal fatto che in presenza di irudina il cleavage della CP è inibito e l’infiammazione articolare nei soggetti con artrite reumatoide è ridotta.

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Tipo di EPrint:Tesi di dottorato
Relatore:De Filippis, Vincenzo
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:28 Gennaio 2014
Anno di Pubblicazione:28 Gennaio 2014
Parole chiave (italiano / inglese):trombina/thrombin, beta2glicoproteinaI/beta2glycoproteinI, alpha-sinucleina/alpha-synuclein, ceruloplasmina/ceruloplasmin
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:6506
Depositato il:03 Nov 2014 09:38
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