Medical protein engineering: understanding macromolecules to defeat diseases

Our research aims at clarifying pathological and physiological features of selected proteins by exploiting protein engineering, structural bioinformatics and X-ray techniques. Building on this information, we design new molecular tools for diagnosis and therapy of human diseases.  We are presently working on five main projects:

(i)    Antibody affinity maturation. In this project, in collaboration with the Growth Factor Group of our Department, we are working to define the structural basis of affinity maturation in the mouse anti-phenyloxazolone system, originally investigated by the Nobel prize Cesar Milstein. In the figure above, crystals of an antibody Fab fragment are shown.

(ii)    L-Asparaginase. We are dissecting this enzyme, used as a drug in pediatric Acute Lymphoblastic Leukemia, in order to clarify both its mechanism of action and the basis of its problematic features, and to generate improved versions of the molecule. In the picture below, a model of the E. coli enzyme is shown with some critical residues highlighted in red.

(iii)   Lipoprotein (a). This protein is a novel cardiovascular risk factor, with a unique inverse relationship between its variable molecular weight, genetically determined by the number of kringle IV type 2 repeats, and its serum concentration. We are now trying to understand biophysical features and pathological potential of these different isotypes.

(iv)   Wnt coreceptors. Wnt pathway is important in development and cancer. In collaboration with the Growth Factor Group of our Department, we are building recombinant domains of key Wnt coreceptors (Ryk, ROR1/2) in order to determine their role in signaling and their potential as anti-cancer drug targets.

(v)   ALK1. In collaboration with the Unit of Human Genetics, we are exploring the protein counterparts of the ACVRL1 gene mutations, which are responsible of Type II Hereditary Hemorrhagic Teleangiectasia. We are very happy to collaborate with other research groups and to accept students for their theses projects.

Selected Papers

Glutaminase activity determines cytotoxicity of L-asparaginases on most leukemia cell lines. Parmentier JH, Maggi M, Tarasco E, Scotti C, Avramis VI, Mittelman SD. Leuk Res 39: 757-62 (2015)

Bioinformatic analysis of pathogenic missense mutations of activin receptor like kinase 1 ectodomain. Scotti C, Olivieri C, Boeri L, Canzonieri C, Ornati F, Buscarini E, Pagella F, Danesino C. PLoS One 6(10):e26431 (2011)

Structural basis of affinity maturation of the TEPC15/Vkappa45.1 anti-2-phenyl-5-oxazolone antibodies. Scotti C and Gherardi E. J Mol Biol 359: 1161-9 (2006)