Utilizing Yeast Surface Human Proteome Display Libraries to Identify Small Molecule-Protein Interactions

  • Scott Bidlingmaier
  • Bin LiuEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1319)


The identification of proteins that interact with small bioactive molecules is a critical but often difficult and time-consuming step in understanding cellular signaling pathways or molecular mechanisms of drug action. Numerous methods for identifying small molecule-interacting proteins have been developed and utilized, including affinity-based purification followed by mass spectrometry analysis, protein microarrays, phage display, and three-hybrid approaches. Although all these methods have been used successfully, there remains a need for additional techniques for analyzing small molecule-protein interactions. A promising method for identifying small molecule-protein interactions is affinity-based selection of yeast surface-displayed human proteome libraries. Large and diverse libraries displaying human protein fragments on the surface of yeast cells have been constructed and subjected to FACS-based enrichment followed by comprehensive exon microarray-based output analysis to identify protein fragments with affinity for small molecule ligands. In a recent example, a proteome-wide search has been successfully carried out to identify cellular proteins binding to the signaling lipids PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Known phosphatidylinositide-binding proteins such as pleckstrin homology domains were identified, as well as many novel interactions. Intriguingly, many novel nuclear phosphatidylinositide-binding proteins were discovered. Although the existence of an independent pool of nuclear phosphatidylinositides has been known about for some time, their functions and mechanism of action remain obscure. Thus, the identification and subsequent study of nuclear phosphatidylinositide-binding proteins is expected to bring new insights to this important biological question. Based on the success with phosphatidylinositides, it is expected that the screening of yeast surface-displayed human proteome libraries will be of general use for the discovery of novel small molecule-protein interactions, thus facilitating the study of cellular signaling pathways and mechanisms of drug action or toxicity.

Key words

Yeast cell surface display cDNA library Small molecule-protein interaction Drug-binding protein Small signaling molecule-binding protein Phosphatidylinositides Chromatin remodeling Transcription regulation Homeobox domain-containing protein 



We thank the National Institutes of Health for financial support (R01 CA118919, R01 CA129491, and R01 CA171315).


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© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Anesthesia, UCSF Helen Diller Family Comprehensive Cancer CenterUniversity of California San FranciscoSan FranciscoUSA

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