The focus of this dissertation is the solution structure of α-syntrophin. I chose α-syntrophin to study as it acts as an adaptor protein plays fundamental roles in eukaryotes....[ Read more ]

The focus of this dissertation is the solution structure of α-syntrophin. I chose α-syntrophin to study as it acts as an adaptor protein plays fundamental roles in eukaryotes.

α-syntrophin is a cytoplasmic adapter protein that associates with dystrophin glycoprotein complex and has putative signaling and structural roles at neuromuscular junctions. The solution structure of N-terminal PH-PDZ tandem domain of α-syntrophin was determined by multidimensional NMR spectroscopy. The PH domain of α-syntrophin adopts a β-sandwich structure capped by a long α-helix on one edge. The PDZ domain of α-syntrophin is composed of a partially opened barrel capped by two α-helices on each open side. The link region of the two domains is mainly random coil except for the carboxyl terminal extension of the PDZ domain. Although the PH domain has a PDZ sequence insertion in its primary structure, its tertiary structure is not affected by the PDZ domain. In the PH-PDZ tandem of α-syntrophin, each domain is well folded, but the orientation between the two domains is not defined due to the lack of inter domain contacts.

We further found that the PH-PDZ tandem of α-syntrophin displays a significantly stronger binding towards phospholipids when compared to the isolated PH and PDZ domains. We conclude that, when covalently connected, the PH and PDZ domains function synergistically in binding to their common partners. The structure of the PH-PDZ tandem derived from this study can provide a mechanistic explanation to the above experimental observation. The data provided in this study reinforce an emerging concept that covalently connected protein-protein interaction domains often function as supra-modules in regulating signal transductions.