Long-range cooperative binding effects in a T cell receptor variable domain

Beenu Moza, Rebecca A. Buonpane, Penny Zhu, Christine A. Herfst, A. K.M. Nur-Ur Rahman, John K. McCormick, David M. Kranz, Eric J. Sundberg

Research output: Contribution to journalArticle

Abstract

Although cellular processes depend on protein-protein interactions, our understanding of molecular recognition between proteins remains far from comprehensive. Protein-protein interfaces are structural and energetic mosaics in which a subset of interfacial residues, called hot spots, contributes disproportionately to the affinity of the complex. These hot-spot residues can be further clustered into hot regions. It has been proposed that binding energetics between residues within a hot region are cooperative, whereas those between hot regions are strictly additive. If this idea held true for all protein-protein interactions, then energetically significant long-range conformational effects would be unlikely to occur. In the present study, we show cooperative binding energetics between distinct hot regions that are separated by >20 Å. Using combinatorial mutagenesis and surface plasmon resonance binding analysis to dissect additivity and cooperativity in a complex formed between a variable domain of a T cell receptor and a bacterial superantigen, we find that combinations of mutations from each of two hot regions exhibited significant cooperative energetics. Their connecting sequence is composed primarily of a single β-strand of the T cell receptor variable Ig domain, which has been observed to undergo a strand-switching event and does not form an integral part of the stabilizing core of this Ig domain. We propose that these cooperative effects are propagated through a dynamic structural network. Cooperativity between hot regions has significant implications for the prediction and inhibition of protein-protein interactions.

Original languageEnglish (US)
Pages (from-to)9867-9872
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number26
DOIs
StatePublished - Jun 27 2006

Keywords

  • Binding energy
  • Cooperativity
  • Protein-protein interaction
  • Surface plasmon resonance
  • T cell activity

ASJC Scopus subject areas

  • General

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  • Cite this

    Moza, B., Buonpane, R. A., Zhu, P., Herfst, C. A., Nur-Ur Rahman, A. K. M., McCormick, J. K., Kranz, D. M., & Sundberg, E. J. (2006). Long-range cooperative binding effects in a T cell receptor variable domain. Proceedings of the National Academy of Sciences of the United States of America, 103(26), 9867-9872. https://doi.org/10.1073/pnas.0600220103