Structural Biology

Biography

Biography: Thomas Scior & Angel Islas

Abstract

The tenet of   homology modeling   relies on the tendency that the divergence of structure directly reflect s the variation in amino acid  sequence identities . Hence the higher the sequenc e identity (homology) between a target and a template structure the more reliable the pred icted target structure should be. This has been a useful paradigm to generate motifs, folds and domains of the proteins that have not been crystallized. Albeit, the study of dynamic  protein-protein interactions  (PPIs) that underpins natural phenomena – gating ions through cell membrane channels in the present case – requires the identification of functional interfaces. Here we demonstrate  how a hitherto unknown PPI can be studied even under extremely low homology conditions (far distant phylogenic relationships) by an analogy  protein modeling . This approach can overcome the problem of structural uncertain ties due to random sequence similarities and can lead to additional insights where three-dimensional data is missing. It proposes – what we call – a common epi-homology feature which is neither structure-bound nor related to protein activity. Eventually, it was the distinction between reversibility and irreversibility of P PIs. The finding enabled us to identify two adjacent amino acids at the postulated reversible interface between two subunits (alpha and beta-1) of the skeletal muscle voltage-gated Na+ channel (Nav1.4). A single side-directed mutagenesis study combined with subsequent electro  physiological characterizations provided the proof of concept and validation. The outcome was a double mutant (T109A, N110A, called TANA for short) that caused the highest loss-of-function effect in the literature (“Identification of Nav β1 residues involved in the modulation of the sodium channel Nav1.4”; Islas AA, Sánchez-Solano A, Scior T, Millan-PerezPeña L, Salinas-Stefanon EM; PLoS One. 8(12): e81995; 2013; “Predicting a double mutant in the twilight zone of low homology modeling for the skeletal muscle voltage-gated sodium channel subunit beta-1 (Nav1.4 β1)”; Scior T, Paiz-Candia B, Islas ÁA, Sánchez-Solano A, Millan-Perez Peña L, Mancilla-Simbro C, Salinas-Stefanon EM; Comput Struct Biotechnol J. 13: 229-240; 2015).