Ricerc@Sapienza

PDZ domains are protein-protein interaction modules involved in dynamic regulation of signalling pathways and scaffolding. They were first observed in synapses of the mammalian nervous system two decades ago and are now regarded to be one of the most common protein domains in eukaryotes, with some 250 distinct PDZ domains in the human genome. They are usually part of multi-domain proteins and can form supramodules either of multiple PDZ domains or with other domains. The PDZ domains selected are: i) the third PDZ domain from PSD-95 (PDZ3) in presence and absence of its C-terminal ¿-helix extension (¿3); ii) the first PDZ domain (PDZ1) of Na+H+ exchange regulatory factor (NHERF); iii) the first and second PDZ domains (PDZ1 and PDZ2) in tandem in a construct of the N-terminal part from whirlin; iv) the third PDZ domain (PDZ3) in a C-terminal proline-rich construct from whirlin. This project aims at describing the folding and binding mechanisms of PDZ domains both in isolation and in the context of multi-domain constructs. In this framework, we will employ site-directed mutagenesis in synergy with biophysical techniques to unravel the molecular details of folding and binding reaction mechanisms.