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• W2920792340 abstract "In silico investigation on protein domains structure and linear/structural motifs can strongly boost functional analyses and technological design.Protein surface features study is crucial to understanding Protein-Protein Interactions (PPI); in particular, surface and pockets conservation and variation, in terms of hydrophobicity, steric hindrance and electrostatics can act as driving forces in protein evolution and functional specialization. Therefore, molecular modeling and structure comparison techniques play an important role in shedding light on “protein behavior” and this PhD work took advantage from integrating computational approaches based on some known molecular modeling methods, such as e.g. Homology Modeling, Fold Recognition, Ab initio Modeling, PBE (Poisson-Boltzmann Electrostatics), Protein-peptide Docking and Hydropathy Analysis with structure and sequence comparison and scanning tools and, of course, with feedback from wet lab analyses performed by co-workers.Such an integrative approach was followed along investigations on a number of different biological systems:•Surface determinants in H5N1 type A Influenza viruses: Here, an analysis of surface determinants from H5N1 haemagglutinin, involved in host-viral interaction, was completed and then published. Genomic variation is very high in influenza A viruses. However, viral evolution and spreading are strongly influenced by immunogenic features and capacity to bind host cells, depending in turn on the two major capsidic proteins (haemagglutinin and neuraminidase). Current analyses of viral evolution are based on serological and primary sequence comparison; however, comparative structural analysis of capsidic proteins can provide functional insights on surface regions possibly crucial to antigenicity and cell binding. We performed molecular modeling and extensive structural comparison of influenza virus haemagglutinin and of their domains and sub-regions to investigate type- and/or domain specific variation. We found that structural closeness and primary sequence similarity are not always tightly related; moreover, type-specific features could be inferred when comparing surface properties of haemagglutinin subregions, monomers and trimers, in terms of electrostatics and hydropathy. Focusing on H5N1, we found that the variation at the receptor binding domain (RBD) surface intriguingly relates to branching of still circulating clades from those ones that are no longer circulating.Recent evidence on the association between electrostatic fingerprints at the haemagglutinin receptor binding surface and the evolutionary success and spreading of H5N1 avian influenza clades prompted us to perform further integrated phylogenetic and structural bioinformatic analysis in H9N2 viruses. In fact, influenza A virus is a zoonotic agent with a significant impact both on public health and poultry industry and switch to human host has been reported for both H5N1 and H9N2 viruses. We performed the evolutionary analysis of a large and non-redundant viral strain dataset, leading to clustering of H9N2 viruses in five groups. Then and according to recent evidence on H5N1, congruence resulted among phylogenetic data and surface electrostatic fingerprints from structural comparison. In particular, surface feature fingerprints could be inferred that relate group specific variation in electrostatic charges and isocontour to well-known hemagglutinin sites involved in modulation of immune escape and host specificity. Results from this second work strengthen suggestion that when integrating up-to-date phylogenetic analyses with sequence-based and structural investigation of surface features may represent a front-end strategy for inferring trends and relevant mechanisms in influenza virus evolution.•Domain architecture variation in mammalian protein trafficking: Human VAMP7b is the most interesting variant among those produced by alternative splicing of the encoding gene SYBL1. Production of VAMP7b variants is determined by skipping of exon 6 which in turn results in coding sequence frameshift. We found that this event is conserved in other mammalian species. VAMP7b shares with the main isoform the N-terminal, inhibitory longin domain and the first half of the SNARE motif. In mammals, VAMP7b is a truncated protein in which the C-terminal half of the SNARE motif and the transmembrane region are replaced by short and variable peptides. Intriguingly instead, only in human and apes sequence frameshift determined by exon 6 skipping results in the creation of a novel unique domain of unknow function, hence human VAMP7b is not truncated but even 40 residues longer than the main isoform. Since existence of such “long” isoform and of its unique domain at protein level were confirmed by specific antibodies, we embarked on in silico dissection of the novel domain by position specific matrix sequence analysis and by ab initio structural modeling. Moreover, since the N-terminal region of the SNARE motif is conserved and it is known to mediate intramolecular binding to the Longin domain, we investigated both in vivo (by two-hybrid in yeast analysis) and in vitro (by NMR analysis) on conservation of the closed conformation. Furthermore, SCL of both VAMP7b and Ykt6b was investigated using GFP and RFP chimeras. Last but not least, b isoforms of the longin genes were analyzed by qPCR and found to be developmentally regulated.•Binding motif regulating neurite outgrowth and guidance: Fine tuning of PPIs by variation in domain architecture or by changing local motifs by surface features modulation can regulate both extracellular and intracellular signaling pathways. Extracellular PPIs can play a central role in heterologous recognition (e.g. host-pathogen) as well as in homologous signaling among cells from the same organism. Proteins exposed at the plasma membrane (PM) can interact each other and with the extracellular matrix (ECM) to provide positional information and guidance cues. Cell adhesion molecules (CAMs) are PM proteins mediating either attractive or repulsive signals by homo- and heterophilic interactions of their extracellular domains (Eds). CAM EDs are most often composed by Ig-like or Fibronectin type III fold repeats. Current evidence suggests that the four N-terminal Ig 1-4 domains of CAM EDs play a major role in such homo- or heterophilic interactions and in particular an important interaction motif is contributed by repeat Ig2. In our lab, biomimetic peptides have been developed by reproducing the known or predicted interaction motifs from the Ig2 domain of human L1CAM and the single Ig domain of human LINGO1, i.e. two proteins that play a crucial role in neurite outgrowth and guidance and in neuronal differentiation. Based on the somehow surprising structural and sequence conservation of the motif region (even when proteins show very different ED architectures), we started investigating on variation and conservation of the putative motif region by means of homology search, regular expression and finally by structural modeling and comparison. Preliminary results highlighted strong conservation of the central Arg residue in the interaction motif, while in other positions of the motif residue properties rather than specific residues are conserved. Such evidence is in agreement with finding that mutation of such residue in L1CAM is responsible for a severe neurological disorder, while mutations at other residues of the motif, results in less severe phenotype. This suggests the motif is an epitope positionally conserved around the central Arg allowing limited, but significant structural variability in surrounding sequence. In order to check such a hypothesis, a structural superposition of the Ig domains containing the interaction motif was performed, confirming that the peptide motif itself is positionally conserved but the highest positional and structural conservation concerns the central Arg residue. Experiments with peptides mutated in the central Arg showed biological activity of these peptides in terms of neuritogenesis signalling.These works carry out a bioinformatic protocol for the characterization of interaction determinants and their functional modulation, easily transportable to other proteins." @default.
• W2920792340 created "2019-03-11" @default.
• W2920792340 creator A5043164000 @default.
• W2920792340 date "2017-07-28" @default.
• W2920792340 modified "2023-09-26" @default.
• W2920792340 title "Towards Systems Biotechnology: identification, characterization and design/engineering of protein interaction motifs/domains mediating regulatory signals" @default.
• W2920792340 hasPublicationYear "2017" @default.
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