An interdomain sector mediating allostery in Hsp70 molecular chaperones.
Allosteric coupling between protein domains is fundamental to many cellular processes. For example, Hsp70 molecular chaperones use ATP binding by their actin-like N-terminal ATPase domain to control substrate interactions in their C-terminal substrate-binding domain, a reaction that is critical for protein folding in cells. Here, we generalize the statistical coupling analysis to simultaneously evaluate co-evolution between protein residues and functional divergence between sequences in protein sub-families. Applying this method in the Hsp70/110 protein family, we identify a sparse but structurally contiguous group of co-evolving residues called a 'sector', which is an attribute of the allosteric Hsp70 sub-family that links the functional sites of the two domains across a specific interdomain interface. Mutagenesis of Escherichia coli DnaK supports the conclusion that this interdomain sector underlies the allosteric coupling in this protein family. The identification of the Hsp70 sector provides a basis for further experiments to understand the mechanism of allostery and introduces the idea that cooperativity between interacting proteins or protein domains can be mediated by shared sectors.
Smock
Robert G
RG
Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA.
Rivoire
Olivier
O
Russ
William P
WP
Swain
Joanna F
JF
Leibler
Stanislas
S
Ranganathan
Rama
R
Gierasch
Lila M
LM
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000495:Allosteric Site; D018407:Bacterial Physiological Phenomena; D002942:Circular Dichroism; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism; D015233:Models, Statistical; D018832:Molecular Chaperones / Q000737:chemistry*; D008968:Molecular Conformation; D016296:Mutagenesis; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism
D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D000251:Adenosine Triphosphatases; C063842:dnaK protein, E coli