Reedel, 18. mail 2012. aastal kell 12 kaitseb Aleksei Lulla Tartu Ülikooli Molekulaar- ja rakubioloogia Instituudis (Riia 23-217) doktoritööd "Alphaviral nonstructural protease and its polyprotein substrate: arrangements for the perfect marriage" (Alfaviiruse mittestruktuurne proteaas ja tema liitvalgust substraat: täiuslikult korraldatud kooselu reeglid) viroloogia erialal.
Juhendaja: TÜ TI professor Andres Merits.
Oponent: professor Ilya Frolov, Alabama Ülikooli mikrobioloogia ja immunoloogia teaduskond, Birmingham, Ameerika Ühendriigid.
Alphaviruses from the Togaviridae family are RNA viruses that may cause arthritic syndroms and encephalitis. The alphavirus replication strategy relies on the production of replicase proteins initially in the form of non-structural (ns) polyprotein precursor P1234, which during the course of replication becomes proteolytically processed by the virus-encoded nsP2 protease in a temporally regulated manner. The studies that constitute the basis of this thesis led to identification of the requirements for substrate specificity of nsP2 protease and revealed novel mechanism for the regulation of processing based on the specific communication between distant parts of the viral polyprotein brought together during assembly of replication complex. It was concluded that the order of alphaviral ns-polyprotein processing is mostly dependent on the configuration of the replication complex imposed by intermolecular interactions meant to guarantee timely cleavages. The alphaviral protease therefore emerges as an integral part of the sophisticated signaling mechanism, in which the regulatory task of the protease consists of monitoring the succession and completion of the events of viral infection. Once the respective replication status-induced conformational changes within replicase allow the presentation of the scissile bond and/or other essential determinants of substrate recognition like exosites, the local protease signaling is initiated, which apparently leads to further reconfiguration of the viral replication complex. Combined, the studies unveiled the decisive role played by the macromolecular assembly-dependent component of substrate recognition in addition to the sequence-dependent component, the combination of which may be expected to constitute the basis of regulation in multi-site proteolytic systems in general. Described findings and their interpretations are expected to provide with essential grounds and directions for further studies on the restriction of alphaviral replication through affecting the center of viral proteolytic activity or via intervention with its regulation by targeting intramolecular interactions.