Evolutionarily conserved networks of residues mediate allosteric communication in proteins.
A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originating at one site in a protein propagate reliably to affect distant functional sites. The general principles of protein structure that underlie this process remain unknown. Here, we describe a sequence-based statistical method for quantitatively mapping the global network of amino acid interactions in a protein. Application of this method for three structurally and functionally distinct protein families (G protein-coupled receptors, the chymotrypsin class of serine proteases and hemoglobins) reveals a surprisingly simple architecture for amino acid interactions in each protein family: a small subset of residues forms physically connected networks that link distant functional sites in the tertiary structure. Although small in number, residues comprising the network show excellent correlation with the large body of mechanistic data available for each family. The data suggest that evolutionarily conserved sparse networks of amino acid interactions represent structural motifs for allosteric communication in proteins.
Süel
Gürol M
GM
Howard Hughes Medical Institute and Department of Pharmacology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9050, USA.
Lockless
Steve W
SW
Wall
Mark A
MA
Ranganathan
Rama
R
D000494:Allosteric Regulation; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002918:Chymotrypsin / Q000737:chemistry / Q000235:genetics; D016000:Cluster Analysis; D017124:Conserved Sequence / Q000235:genetics*; D030562:Databases, Protein; D019143:Evolution, Molecular; D006454:Hemoglobins / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D015233:Models, Statistical; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics
D000596:Amino Acids; D006454:Hemoglobins; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D012697:Serine Endopeptidases; D002918:Chymotrypsin