Principal Component Analysis of the Conformational Freedom within the EF-Hand Superfamily

Abstract

A database of nonredundant structures of EF-hand domains--i.e., pairs of helix-loop-helix motifs--has been assembled, and the six angles among the four helices re-determined. A principal component analysis of these angles allows us to use two such components (PC1 and PC2) to describe the system retaining 80% of the total variance. A PC2 against PC1 plot representation allows us to represent in a compact way the full range of structural diversity of EF-hand domains, their grouping into protein families, and the variation for each family upon calcium and peptide binding.

Structural Basis for Diversity of the EF-hand Calcium-binding Proteins

“…127 Also a broad distribution of interhelical angles was found in the most recent analysis of a large database containing 307 two-EF-hand domains. 128 These observations underscore the exceptional structural versatility of the EF-hand motif, which apparently has the capacity to function in a very broad conformational landscape.…”

Sampling small-scale and large-scale conformational changes in proteins and molecular complexes

“…4,[35][36][37] This independent unit is subjected to a series of 100 events. This domain is known to display different bundles of helices upon calcium binding.…”

“…1͑a͒ and 1͑b͒, we show the variations of the six interhelical angles calculated using the procedure described in Babini et al 4 as a function of all generated ARTIST events with the helices held rigid. 1͑a͒ and 1͑b͒, we show the variations of the six interhelical angles calculated using the procedure described in Babini et al 4 as a function of all generated ARTIST events with the helices held rigid.…”

“…In the context of computational biology, such problems include protein folding and aggregation, protein-protein docking, ligand binding, DNA-protein binding, and many others. 4 Similarly, protein kinases display an inherent plasticity in response to interactions with specific partners and can reveal atomic displacements of specific regions by 10-15 Å from their unbounded states. 1,2 In the case where the protein displacement is limited to a few residues within the catalytic pocket and the structure of the target protein with a similar ligand is available, a rigid treatment of the protein backbone is not a severe limitation, simplifying considerably the theoretical treatment.…”

Conformational dynamics associated with calcium binding to calcium transducers

“…There are some proteins that contain an odd number of EF-hands, for example a voltage gated Ca 2 + channel has a single functional EF-hand (Bunet et al 2005). Parvalbumin contains three EF-hands but the unpaired EFhand is not functional (Babini et al 2005). The EF-hands, apart from acting as Ca2+ binding sites, are also involved in promoting protein dimerization as seen in case of five EF-hand containing proteins like calpain, in which the fifth EF-hand gets paired up with a corresponding single EF-hand presented on the second monomer (Blanchard et al 1997, Jia et al 2001, Ilari et al 2002, Jia et al 2000, Reid et al 1990, Shaw et al 1990, Shaw et al 1992).…”