Reassessing a sparse energetic network within a single protein domain

doi:10.1073/pnas.0711732105

Reassessing a sparse energetic network within a single protein domain

*Department of Medical Biochemistry and Microbiology, Uppsala University Biomedical Centre, Box 582, SE-751 23 Uppsala, Sweden; and
^†Department of Ecology, Swedish University of Agricultural Sciences, P.O. Box 7044, SE-750 07 Uppsala, Sweden

Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom, and approved January 22, 2008 (received for review December 13, 2007)

Abstract

Understanding the molecular principles that govern allosteric communication is an important goal in protein science. One way allostery could be transmitted is via sparse energetic networks of residues, and one such evolutionary conserved network was identified in the PDZ domain family of proteins by multiple sequence alignment [Lockless SW, Ranganathan R (1999) Science 286:295–299]. We have reassessed the energetic coupling of these residues by double mutant cycles together with ligand binding and stability experiments and found that coupling is not a special property of the coevolved network of residues in PDZ domains. The observed coupling for ligand binding is better explained by a distance relationship, where residues close in space are more likely to couple than distal residues. Our study demonstrates that statistical coupling from sequence analysis is not necessarily a reporter of energetic coupling and allostery.

Footnotes

^‡To whom correspondence should be addressed. E-mail: per.jemth{at}imbim.uu.se
Author contributions: C.N.C., L.E., Y.S., and P.J. designed research; C.N.C., L.E., Y.S., and Å.E. performed research; C.N.C., L.E., Y.S., T.S., Å.E., and P.J. analyzed data; and C.N.C., T.S., and P.J. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711732105/DC1.