Faculty

Website: http://www.people.ku.edu/~johnk

Cytokines are small secreted proteins responsible for mediating cell-cell communication. A given cytokine can bring together different combinations of cell-surface receptors on different cell types, to elicit a series of cell-specific responses; this property is known as pleiotropy. The encoding of multiple functions in a single cytokine has confounded attempts to understand—and manipulate—cell–cell signaling.

The Karanicolas lab is working towards building up a map of cytokine–receptor interactions using computational structure-based docking, and experimentally validating predicted interactions in vitro and in vivo. Where specific examples of cytokines that functionally bind more than one receptor complex are identified, computational protein design is used to develop variants of these cytokines which are selective for a single receptor complex. Further, we use de novo protein design techniques to engineer new proteins which restrict the cytokine to a specific function, by occluding surfaces responsible for pleiotropy. Both classes of designed proteins are tested in vivo.

We are also developing methodology for computationally exploring small motions on cytokine surfaces, by biasing the search to reveal binding pockets suitable for small-molecules. Computational methods will then be applied to screen for small-molecule fragments which fit into these emergent pockets. These fragments will be combined to identify compounds that inhibit specific cytokine–receptor interactions in vitro and in vivo. These compounds we identify will be used to further deconvolute cytokine signaling networks, and will be explored as potential therapeutics.

Collectively, these goals utilize a structural understanding of cytokine–receptor interactions to attenuate certain cytokine functions while leaving others intact. This research is designed to extend the current understanding of cell-cell communication, and to stimulate novel therapeutic approaches for human conditions ranging from cancer to allergic inflammation.

Representative Publications

• Karanicolas J., Joachimiak L.A., Corn J.E., Hu W., and Baker D. “Computational design of a de novo protein-protein interface” (manuscript in preparation).
• Karanicolas J., Sievers S.A., Baker D., and Eisenberg D. “Structure-based design of D-amino acid peptide inhibitors of tau fibrillation” (submitted).
• Karanicolas, J. and Kuhlman, B. Computational Design of Affinity and Specificity at Protein-Protein Interfaces (submitted).
• Luo B.-H., Karanicolas J., Harmacek L.D., Baker D., and Springer T.A. “Rational design of integrin β3 mutations stabilized in the high affinity conformation” J. Biol. Chem., 284, p. 3917 (2009).
• Thompson M.J., Sievers S.A., Karanicolas J., Ivanova M.I., Baker D., and Eisenberg D. “The 3D profile method for identifying fibril-forming segments of proteins” Proc. Natl. Acad. Sci. USA, 103, p. 4074 (2006).

Search PubMed for articles by John Karanicolas.