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PONTAROLLO, GIULIA (2017) Molecular Mechanisms of Recognition of Coagulation Factors
(Meccanismi Molecolari di Riconoscimento dei Fattori della Coagulazione).
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Abstract (inglese)

The biochemical pathways sustaining living organisms, traditionally regarded as independently organized systems, are actually extensively connected by non-canonical protein interactions. The disruption of this finely regulated homeostasis, largely yet to unravel, results in various pathological manifestations.
Haemostasis (Chapter 1) is a defence response triggering after vessel walls injuries, which is articulated in the cascade activation of the blood coagulation factors, resulting in the generation of a localized clot. The central reaction of the coagulation cascade is prothrombin activation to mature a-thrombin by FXa, through the generation of the physiologically relevant intermediate prethrombin-2. Active a-thrombin is an ellipsoidal protein, composed of two six-stranded b-barrels encompassing, at their interface, the catalytic triad (His57, Asp102, Ser195). Opposite to the negatively charged active site, two extra positive regions of binding, named exosite I and exosite II, mediate the recognition with several physiologic ligands and substrates. Mature a-thrombin plays a pivotal role in haemostasis, entailing both procoagulant functions (platelets aggregation, fibrin generation) and an anticoagulant one (protein C activation). Beyond coagulation, this serine protease acts at the interface between inflammation, cellular proliferation, and neurodegenerative diseases.
The interplay between a-thrombin and proteins traditionally belonging to the central nervous system is undoubtedly a pioneering and yet unexplored topic (Chapter 2.1). When present at high cerebral concentrations a-thrombin triggers a pathologic pro-inflammatory state in the brain, which may be involved in the onset of neurodegenerative diseases. In detail, we refer to as synucleinopathies for a branch of diseases (i.e. Parkinson’s disease) in which intracellular proteinaceous aggregates, mainly composed of a-synuclein, localize both in neurons and in glia. a-synuclein is an abundant presynaptic protein, belonging to the family of naturally unfolded proteins (NUPs), whose physiologic function is still matter of debate. Strikingly, beyond central nervous system, a-synuclein has been detected in plasma and in the haematopoietic lineage, particularly in platelets. Surprisingly, patients suffering from Parkinson’s disease, featuring high a-synuclein concentrations, are characterized by lower ischaemic attacks, due to platelets abnormalities and impaired aggregation. Being these cells the main trigger of a-thrombin, we purposed to investigate the interaction between this enzyme and a-synuclein (Chapter 2.2). Our data clearly demonstrate that the two proteins bind with an affinity physiologically relevant for the concentrated microenvironment surrounding platelets. In the binary complex, a-synuclein interacts promiscuously with a-thrombin exosites by its negatively charged de-structured C-terminus, thus scavenging hyper-aggregation phaenomena.
In this intricate network, positive upregulation between coagulation and inflammation has been well established and extensively studied (Chapter 3.1). During sepsis, systematically activated immune response results in an exaggerated and detrimental inflammation, usually coupled to disseminated intravascular coagulation. In this scenario, exogenous proteases may play a relevant role during the early stages of the infection by directly activating coagulation. Several pathogen microorganisms express and secrete subtilisin-like serine proteases (subtilases), characterized by a broad specificity of cleavage. We purposed to investigate the effects of subtilases-catalysed proteolysis of thrombin zymogens prethrombin-2 (Chapter 3.2) and prothrombin (Chapter 3.3) by using the commercially available subtilisin Carlsberg, as a prototype for the superfamily. From the proteolysis and enzymatic assays data, it strikingly emerged that subtilisin activates both the zymogens to a novel thrombin-like specie, by the non-canonical hydrolysis of Ala470(149a)-Asn471(149b) peptide bond. The novel active specie, we named sPre2, is a non-covalent complex featuring the same a-thrombin cleavage specificity, with a catalytic efficiency ≈150-fold inferior to the physiologic enzyme. From fluorescence titrations and surface binding resonance, it emerged that sPre2 is characterized by a fully competent exosite II, an imperfect exosite I and a correctly moulded active site, which however features an impaired mechanism of substrate conversion.
Both experimental and clinical evidences clearly demonstrate the crucial importance of maintaining coagulation homeostasis, which, in physiologic conditions, is slightly unbalanced towards a haemorrhagic state to keep blood fluid in the intact vessels. A disruption of this equilibrium due to increase of functioning leads to pathological manifestations generically referred to as thrombosis (Chapter 4.1). Unfortunately, classical anticoagulant therapy presents well-documented limitations and bleeding side effects, driving the continuous efforts to develop new, safer drugs. In the late years, a hot research topic is represented by the engineering of natural anticoagulants from hematophagous organisms. Among all, anticoagulant hirudin from the medicinal leeches is the most popular compound, being a-thrombin most potent and specific natural inhibitor. In this work, we propose a novel strategy for hirudin production in E. coli, by conjugation to SUMO (small ubiquitin-like modifier protein), a eukaryotic chaperon which enhances protein folding and solubility (Chapter 4.2). The so-obtained recombinant hirudin is characterized by the same folding, spectroscopic features, and anti-thrombin activity of the natural variant.
In conclusion, coagulation is undoubtedly one of the most articulated and fascinating physio-pathologic systems regulating body homeostasis, displaying several connections with other biochemical pathways. The molecular mechanisms of recognition of the coagulation factors, yielding traditional or original protein interactions, is still a highly unexplored topic.

Abstract (italiano)

I processi biochimici che sorreggono gli organismi viventi, tradizionalmente considerati come sistemi chiusi e indipendenti, sono in realtà estensivamente collegati da interazioni proteiche non canoniche in gran parte non ancora individuate. Minimi squilibri in questo network finemente regolato possono scaturire in svariate manifestazioni patologiche.
Il processo di difesa che si innesca a seguito di lesioni alle pareti vascolari, denominato emostasi (Capitolo 1), si articola nell’attivazione a catena dei fattori della coagulazione, con la generazione di un coagulo localizzato al sito di danno. La reazione centrale della cascata della coagulazione è l’attivazione della protrombina ad a-trombina da parte del FXa, attraverso la generazione dell’intermedio pretrombina-2, fisiologicamente rilevante. L’a-trombina matura è una proteina ellissoidale, composta da due b-barrel a sei filamenti che circoscrivono, alla loro interfaccia, la triade catalitica carica negativamente (His57, Asp102, Sar195). Ai lati del sito attivo, in due regioni diametralmente opposte, sono situate due siti carichi positivamente, denominati esosito I ed esosito II. Queste due extra superfici di riconoscimento mediano l’interazione con diversi substrati e ligandi fisiologici. L’a-trombina gioca un ruolo chiave nella regolazione dell’emostasi, svolgendo sia funzioni procoagulanti (aggregazione piastrinica, generazione di fibrina) che paradossalmente anticoagulanti (attivazione della proteina C). Questo enzima opera inoltre all’interfaccia tra infiammazione, proliferazione cellulare e malattie neurodegenerative.
La correlazione tra a-trombina e proteine del sistema nervoso centrale è senza dubbio un ambito di studi innovativo (Capitolo 2.1). Quando presente ad alte concentrazioni cerebrali l’a-trombina innesca uno stato pro-infiammatorio nel cervello, potenzialmente coinvolto nell’insorgenza di malattie neurodegenerative. In particolare, il termine sinucleinopatie è riferito a un insieme di patologie (fra tutte il morbo di Parkinson) in cui aggregati proteici intracellulari, composti principalmente di a-sinucleina, si accumulano a livello di neuroni e cellule della glia. L’a-sinucleina è un’abbondante proteina presinaptica appartenente alla famiglia delle NUPs (naturally unfolded proteins), la cui funzione fisiologica è tuttora oggetto di dibattito. Sorprendentemente, questa proteina altamente conservata è stata rilevata anche nel plasma e a livello delle cellule ematopoietiche, in particolar modo nelle piastrine. Studi clinici dimostrano che i pazienti affetti da morbo di Parkinson, caratterizzati da elevate concentrazioni di a-sinucleina, presentano minori attacchi ischemici, dovuti a ridotta aggregazione piastrinica. Poiché le piastrine rappresentano il bersaglio cellulare per eccellenza dell’a-trombina, abbiamo orientato il nostro lavoro nello studio dell’interazione tra questo enzima e l’a-sinucleina (Capitolo 2.2). I nostri dati sperimentali dimostrano chiaramente che i due partner interagiscono in un complesso binario in cui l’a-sinucleina lega entrambi gli esositi dell’a-trombina, con la sua estremità C-terminale carica negativamente. La costante di affinità, fisiologicamente rilevante nel microambiente concentrato che circonda la superficie piastrinica, giustificherebbe lo scavenging da parte dell’a-sinucleina dei processi di iper-aggregazione.
In questa intricata rete di collegamenti, il feedback positivo tra coagulazione e infiammazione è stato ampiamente descritto (Capitolo 3.1). Durante i fenomeni di setticemia, la risposta infiammatoria viene costitutivamente attivata nel tentativo di combattere un agente patogeno esterno. Questa condizione degenera in uno stato pro-infiammatorio distruttivo per l’ospite stesso, spesso accoppiato a fenomeni di coagulazione disseminata intravascolare. In questo scenario, le proteasi secrete da organismi esogeni potrebbero giocare un ruolo rilevante durante le prima fasi dell’infezione attraverso l’attivazione diretta della cascata coagulativa. Svariati microorganismi patogeni esprimono e secernono proteasi subtilisin-like (famiglia delle subtilasi), caratterizzate da un’ampia aspecificità di taglio. Ci siamo quindi focalizzati nello studio della proteolisi degli zimogeni inattivi dell’a-trombina umana, pretrombina-2 (Capitolo 3.2) e protrombina (Capitolo 3.3), da parte delle subtilasi di origine batterica. In particolare, la subtilisina Carlsberg, ampiamente caratterizzata e commercialmente disponibile, è stata utilizzata come prototipo di tutta la superfamiglia. A partire dai dati sperimentali di proteolisi e attività enzimatica è emerso che la subtilisina attiva entrambi gli zimogeni a una nuova specie trombino-simile, attraverso l’idrolisi del legame peptidico Ala470(149a)-Asn471(149b). La nuova specie attiva, denominata sPre2, è un complesso non covalente, caratterizzato dalla stessa specificità di idrolisi dell’a-trombina, con un’efficienza catalitica ≈150 volte inferiore all’enzima wild type. Dalla mappatura eseguita mediante saggi di fluorescenza e risonanza plasmonica di superficie è emerso che la sPre2 è caratterizzata da un esosito II perfettamente formato, un esosito I imperfetto e da un sito attivo correttamente formato, che tuttavia presenta dei deficit nel processo di conversione dei substrati fisiologici dell’a-trombina in prodotti.
Sia i dati clinici che le evidenze sperimentali dimostrano l’importanza cruciale del mantenimento dell’omeostasi nella coagulazione, che, in condizioni fisiologiche, è leggermente sbilanciata verso uno stato emorragico, per mantenere la fluidità del sangue nei vasi sanguigni intatti. Una rottura di questo equilibrio dovuto a un aumento di funzionalità porta a manifestazioni patologiche genericamente riferite come trombosi (Capitolo 4.1). Sfortunatamente, la terapia anticoagulante classica presenta limitazioni ed effetti collaterali di sanguinamento ben documentati. Negli ultimi anni, un nuovo trend di ricerca è rappresentato dall’ingegnerizzazione di anticoagulanti naturali da organismi ematofagi. Tra tutti, l’anticoagulante irudina, originariamente estratto dalle sanguisughe medicinali, è il composto più popolare, essendo l’inibitore dell’a-trombina più potente e specifico in natura. In questo lavoro di Tesi proponiamo una nuova strategia di produzione dell’irudina ricombinante, attraverso la coniugazione a SUMO (small ubiquitin-like modifier protein), una proteina chaperone eucariotica, coadiuvante nel folding e nella solubilizzazione proteica (Capitolo 4.2). L’irudina ricombinante prodotta con questa strategia è caratterizzata dalle stesse proprietà spettroscopiche e attività inibitoria della variante naturale.
In conclusione, la coagulazione è senza dubbio uno dei sistemi fisio-patologici più affascinanti e articolati, presentando diverse connessioni con differenti pathway biochimici. I meccanismi molecolari di riconoscimento dei fattori della coagulazione nell’interazione con proteine tradizionali o alternative è un argomento ancora largamente inesplorato.

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Tipo di EPrint:Tesi di dottorato
Relatore:DE FILIPPIS, VINCENZO
Dottorato (corsi e scuole):Ciclo 29 > Corsi 29 > SCIENZE MOLECOLARI
Data di deposito della tesi:30 Gennaio 2017
Anno di Pubblicazione:26 Gennaio 2017
Parole chiave (italiano / inglese):thrombin, prothrombin, a-synuclein, subtilisin, hirudin, SUMO, sepsis, neurodegeneration, platelets, anticoagulants,
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:9969
Depositato il:24 Nov 2017 09:52
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