α-Dystroglycan at the ECM-Cell crossroad: emerging functions of its N-terminal domain

: Dystroglycan plays a crucial role for cell to extracellular matrix (ECM) adhesiveness in a plethora of different tissues and physio-pathological conditions. It belongs to the dystrophin-glycoprotein complex, whose overall structure has been recently solved, providing fundamental insight into the assembly of its various protein components, including the dystroglycan complex. This inspired us to embark in a timely "recollection journey" of our studies on the dystroglycan domain organization, mainly focusing on the targeted mutagenesis analysis of the α-dystroglycan's N-terminal domain (α-DGN) that we have carried out during the last 30 years. The account of such a journey also reinforces a crucial notion in protein biochemistry: a single amino acid substitution can lead to a significantly improved stability of the whole protein. Over-stabilizing matrix proteins, and proteins in general, has positive repercussions for the study of their structural and functional properties, and it is a crucial tool for developing biotechnological applications. Here we discuss newly emerged data along a series of yet unresolved points concerning the biochemical features and biological role of α-DGN, as well as the possible biomedical use recently emerged for a stabilized single site-directed variant of this protein domain.