The switch helix: A putative combinatorial relay for interprotomer communication in cGMP-dependent protein kinase

• Published in: Biochimica et biophysica acta 2013-07, Vol.1834 (7), p.1346-1351
• Main Authors: Moon, Thomas M., Osborne, Brent W., Dostmann, Wolfgang R.
• Format: Article
• Language: English
• Subjects: Allostery; Amino Acid Sequence; cAMP; cAMP-dependent protein kinase; cGMP; cGMP-dependent protein kinase; Crystal structure; cyclic GMP; Cyclic GMP - chemistry; Cyclic GMP - metabolism; Cyclic GMP-Dependent Protein Kinases - chemistry; Cyclic GMP-Dependent Protein Kinases - genetics; Cyclic GMP-Dependent Protein Kinases - metabolism; Humans; hydrophobicity; isozymes; loci; methodology; Models, Molecular; Molecular Sequence Data; PKG; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; protein subunits; Quaternary structure; Sequence Homology, Amino Acid
• ISSN: 1570-9639; 0006-3002; 1878-1454
• DOI: 10.1016/j.bbapap.2013.02.009

For over three decades the isozymes of cGMP-dependent protein kinase (PKG) have been studied using an array of biochemical and biophysical techniques. When compared to its closest cousin, cAMP-dependent protein kinase (PKA), these studies revealed a set of identical domain types, yet containing distinct, sequence-specific features. The recently solved structure of the PKG regulatory domain showed the presence of the switch helix (SW), a novel motif that promotes the formation of a domain-swapped dimer in the asymmetric unit. This dimer is mediated by the interaction of a knob motif on the C-terminal locus of the SW, with a hydrophobic nest on the opposing protomer. This nest sits adjacent to the cGMP binding pocket of the B-site. Priming of this site by cGMP may influence the geometry of the hydrophobic nest. Moreover, this unique interaction may have wide implications for the architecture of the inactive and active forms of PKG. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases (2012). ► The SW adopts an energetically-favorable interaction between opposing protomers. ► The interaction sites for the SW are conserved in type I, but not type II isoforms. ► Cyclic nucleotide binding may lead to remodeling of the interaction site for SW. ► The SW configuration may indicate an induced mechanism of activation.