Solution structure of the N-terminal A domain of the human voltage-gated Ca2+channel β4a subunit

Ca2+ channel β subunits regulate trafficking and gating (opening and closing) of voltage-dependent Ca2+ channel α 1 subunits. Based on primary sequence comparisons, they are thought to be modular structures composed of five domains (A–E) that are related to the large family of membrane associated guanylate-kinase (MAGUK) proteins. The crystal structures of the β subunit core, B–D, domains have recently been reported; however, very little is known about the structures of the A and E domains. The N-terminal A domain is a hypervariable region that differs among the four subtypes of Ca2+ channel β subunits (β1–β4). Furthermore, this domain undergoes alternative splicing to create multiple N-terminal structures within a given gene class that have distinct effects on gating. We have solved the solution structure of the A domain of the human β4a subunit, a splice variant that we have shown previously to have α 1 subunit subtype-specific effects on Ca2+ channel trafficking and gating