Our research group is broadly interested in peptide-binding domains and how only a small number of amino acids are recognized in a given interaction. Specifically, we are focused on the PDZ domain, which is important in signaling and trafficking pathways in the cell. There are over 200 PDZ domains in the human proteome, making it the largest family of peptide-binding domains. Defined motifs include only a couple of positions along the peptide-binding cleft, and do not accurately define the overlapping yet distinct preferences among family members. Our research group will work to understand the selectivity determinants of PDZ domains throughout evolution. We will use biochemistry and structural biology to investigate PDZ domains from extant species, as well as by using ancestral protein reconstruction. We are also interested in the selectivity determinants of other peptide-binding domains, e.g., the SH2 domain, which binds phosphorylated tyrosine-containing peptides.
Educational & Professional Experience
- B.S. Physics, University of Oregon, 2007.
- Ph.D. Biochemistry, Geisel School of Medicine at Dartmouth, 2014.
- Postdoctoral Fellow, University of California, Berkeley, 2014-2017.
- Jane Coffin Childs Memorial Fund for Medical Research Postdoctoral Fellow, University of California, Berkeley, 2015-2017.
Shah NH, Amacher JF, Nocka L, Kuriyan J. The Src module: an ancient scaffold in the evolution of cytoplasmic tyrosine kinases. Crit Rev Biochem Mol Biol. 2018. Sep 5: 1-29. Review.
Amacher JF, Hobbs HT, Cantor AC, Shah L, Rivero MJ, Mulchand SA, Kuriyan J. Phosphorylation control of the ubiquitin ligase Cbl is conserved in choanoflagellates. Protein Sci. 2018. 27(5): 923-32.
Courtney AH, Amacher JF, Kadlecek TA, Mollenauer MN, Au-Yeung BB, Kuriyan J, Weiss A. A Phosphosite within the SH2 Domain of Lck Regulates Its Activation by CD45. Mol Cell. 2017. 67(3):498-511
Amacher JF, Zhong F, Lisi GP, Zhu MQ, Alden SL, Hoke KR, Madden DR, Pletneva EV. A Compact Structure of Cytochrome c Trapped in a Lysine-Ligated State: Loop Refolding and Functional Implications of a Conformational Switch. J Am Chem Soc. 2015. 137(26):8435-49.
Qian Z, Xu X, Amacher JF, Madden DR, Cormet-Boyaka E, Pei D. Intracellular Delivery of Peptidyl Ligands by Reversible Cyclization: Discovery of a PDZ Domain Inhibitor that Rescues CFTR Activity. Angew Chem. 2015. 54(20):5874-8.
Amacher JF, Zhao R, Spaller MR, Madden DR. Chemically modified peptide scaffolds target the CFTR-associated ligand PDZ domain. PLoS One. 2014. 9(8):e103650.
Amacher JF, Cushing PR, Brooks L 3rd, Boisguerin P, Madden DR. Stereochemical preferences modulate affinity and selectivity among five PDZ domains that bind CFTR: comparative structural and sequence analyses. Structure. 2014. 22(1):82-93.
Amacher JF, Cushing PR, Bahl CD, Beck T, Madden DR. Stereochemical determinants of C-terminal specificity in PDZ peptide-binding domains: a novel contribution of the carboxylate-binding loop. J Biol Chem. 2013. 288(7):5114-26.