Journal Article

Differences in intradomain and interdomain motion confer distinct activation properties to structurally similar Galpha proteins

Jones, Janice C, Jones, Alan M, Temple, Brenda R S, Dohlman, Henrik G

2012

Overview

Proteins with similar crystal structures can have dissimilar rates of substrate binding and catalysis. Here we used molecular dynamics simulations and biochemical analysis to determine the role of intradomain and interdomain motions in conferring distinct activation rates to two Gα proteins, Gα^sub i1^ and GPA1. Despite high structural similarity, GPA1 can activate itself without a receptor, whereas Gα^sub i1^ cannot. We found that motions in these proteins vary greatly in type and frequency. Whereas motion is greatest in the Ras domain of Gα^sub i1^, it is greatest in helices αA and αB from the helical domain of GPA1. Using protein chimeras, we show that helix αA from GPA1 is sufficient to confer rapid activation to Gα^sub i1^. Gα^sub i1^ has less intradomain motion than GPA1 and instead displays interdomain displacement resembling that observed in a receptor-heterotrimer crystal complex. Thus, structurally similar proteins can have distinct atomic motions that confer distinct activation mechanisms. [PUBLICATION ABSTRACT]

• Publisher: National Academy of Sciences
• Subject: Biochemical analysis / Biochemistry / Catalysis / Computer simulation / Crystal structure / Proteins