Comprehensive and quantitative mapping of energy landscapes for protein-protein interactions by rapid combinatorial scanning

G. Pál, Jean Louis K Kouadio, Dean R. Artis, Anthony A. Kossiakoff, Sachdev S. Sidhu

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

A novel, quantitative saturation (QS) scanning strategy was developed to obtain a comprehensive data base of the structural and functional effects of all possible mutations across a large protein-protein interface. The QS scan approach was applied to the high affinity site of human growth hormone (hGH) for binding to its receptor (hGHR). Although the published structure-function data base describing this system is probably the most extensive for any large protein-protein interface, it is nonetheless too sparse to accurately describe the nature of the energetics governing the interaction. Our comprehensive data base affords a complete view of the binding site and provides important new insights into the general principles underlying protein-protein interactions. The hGH binding interface is highly adaptable to mutations, but the nature of the tolerated mutations challenges generally accepted views about the evolutionary and biophysical pressures governing protein-protein interactions. Many substitutions that would be considered chemically conservative are not tolerated, while conversely, many non-conservative substitutions can be accommodated. Furthermore, conservation across species is a poor predictor of the chemical character of tolerated substitutions across the interface. Numerous deviations from generally accepted expectations indicate that mutational tolerance is highly context dependent and, furthermore, cannot be predicted by our current knowledge base. The type of data produced by the comprehensive QS scan can fill the gaps in the structure-function matrix. The compilation of analogous data bases from studies of other protein-protein interactions should greatly aid the development of computational methods for explaining and designing molecular recognition.

Original languageEnglish
Pages (from-to)22378-22385
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number31
DOIs
Publication statusPublished - Aug 4 2006

Fingerprint

Scanning
Proteins
Databases
Substitution reactions
Human Growth Hormone
Mutation
Molecular recognition
Knowledge Bases
Computational methods
Conservation
Binding Sites
Pressure

ASJC Scopus subject areas

  • Biochemistry

Cite this

Comprehensive and quantitative mapping of energy landscapes for protein-protein interactions by rapid combinatorial scanning. / Pál, G.; Kouadio, Jean Louis K; Artis, Dean R.; Kossiakoff, Anthony A.; Sidhu, Sachdev S.

In: Journal of Biological Chemistry, Vol. 281, No. 31, 04.08.2006, p. 22378-22385.

Research output: Contribution to journalArticle

Pál, G. ; Kouadio, Jean Louis K ; Artis, Dean R. ; Kossiakoff, Anthony A. ; Sidhu, Sachdev S. / Comprehensive and quantitative mapping of energy landscapes for protein-protein interactions by rapid combinatorial scanning. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 31. pp. 22378-22385.
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