Blake Hill Associate Professor Department of Biology CMDB Graduate Program Faculty B.A. Kalamazoo College Ph.D. Yale University Postdoctoral University of Pennsylvania

RESEARCH INTERESTS

The long-term goal of our lab is to contribute to understanding the molecular basis of disease. This goal requires knowledge about many fundamental biological processes that can malfunction to cause disease. Our lab focuses on two of these fundamental biological processes: protein folding and intracellular communication. Improper protein folding and improper intracellular communication are both known to result in a wide variety of diseases that range from cancer to Alzheimer's disease. The questions we are addressing are:

1. How do proteins fold into their biologically active conformation?
2. How do proteins regulate intracellular communication?

Protein Folding

Proteins are synthesized as a linear chain of amino acids but are usually not active until they fold into a unique conformation that is typically compact . We believe in a protein folding code that dictates how a protein folds into its biologically active conformation. To test our understanding of this protein folding code, we design an amino acid sequence that will fold into a desired conformation. We then produce the protein chemically or biologically, and characterize its structure and thermodynamic properties using NMR spectroscopy, circular dichroism spectroscopy, fluorescence spectroscopy, calorimetry, and analytical ultracentrifugation. This iterative process of design and production of a protein followed by rigorous biophysical characterization is called de novo protein design and allows us to refine the protein folding code.

Intracellular Communication Networks

Life requires proper communication. Communication networks exist within a cell that allows for proper cell life. This intracellular communication involves a complex network of interactions between proteins and other biomolecules. Many of these networks are composed of protein-protein interactions that need to be tightly regulated for proper cell life. To understand how these networks are regulated, we will isolate proteins known to regulate intracellular communication networks and determine their structural, thermodynamic, and kinetic properties. The results of this work will identify essential features involved in the misregulation of these networks and identify possible therapeutic routes.

SELECTED PUBLICATIONS

Tan, F., Fire, A., and Hill R. B. 2007. Regulation of apoptosis by C. elegans CED-9 in the absence of the C-terminal transmembrane domain. Cell Death and Differentiation. (In Press.)

F.J. Tan, J.E. Zuckerman, A.Z. Fire, and R.B. Hill. 2007. Regulation of apoptosis by C. elegans CED-9 in the absence of the C-terminal transmembrane domain. Cell Death Differ . 14:1925-35.

R.C. Wells, L.K. Picton, S.C.P. Williams, F.J. Tan, and R.B. Hill. 2007. Direct binding of the dynamin-like GTPase, Dnm1, to mitochondrial dynamics protein Fis1 is negatively regulated by the Fis1 N-terminal arm. J Mol Biol. 359(4):1045-58. EpubApr 6.

G.R. Thuduppathy, O. Terrones, J. W. Craig, G. Basañez, and R.B. Hill. 2006. The N-terminal domain of Bcl-xL reversibly binds membranes in a pH-dependent manner. J Biochemistry. 45:14533-42.

Thuduppathy GR, Craig JW, Kholodenko V, Schon A, Hill RB. 2006. Evidence that membrane insertion of the cytosolic domain of Bcl-xL is governed by an electrostatic mechanism. J Mol Biol. 359(4):1045-58. EpubApr 6.

Thuduppathy GR, Hill RB. 2006. Acid destabilization of the solution conformation of Bcl-xL does not drive its pH-dependent insertion into membranes. Protein Sci. 15(2):248-57. Epub 2005 Dec 29.

Fannjiang Y, Cheng WC, Lee SJ, Qi B, Pevsner J, McCaffery JM, Hill RB, Basanez G, Hardwick JM.2004. Mitochondrial fission proteins regulate programmed cell death in yeast. Genes Dev. 18(22):2785-97. Epub 2004 Nov 1.

Thuduppathy GR, Hill RB. 2004. Applications of NMR spin relaxation methods for measuring biological motions. Methods Enzymol.384:243-64. No abstract available.

Dohm JA, Lee SJ, Hardwick JM, Hill RB, Gittis AG. 2004. Cytosolic domain of the human mitochondrial fission protein fis1 adopts a TPR fold. Proteins. 54(1):153-6. No abstract available.

David Salom, R. Blake Hill, James D. Lear, and William F. DeGrado. 2000. Protons versus Amantadine: A competition for binding to the M2 tetrameric ion channel from Influenza A virus. Biochemistry, 39, 14160-14170.

R. Blake Hill, Daniel P. Raleigh, Angela Lombardi, and William F. DeGrado. 2000. De novo design of helical bundles as models for understanding protein folding and function. Acc. Chem. Res., 33, 745-754.

R. Blake Hill, Clay Bracken, William F. DeGrado, and Arthur G. Palmer III. 2000. Molecular motions and protein folding: Characterization of the backbone dynamics and folding equilibrium of a2D using ¹³C NMR spin relaxation. J. Am. Chem. Soc., 122, 11610-11619.

R. Blake Hill and William F. DeGrado. 2000. A polar, solvent-exposed residue can be essential for native protein structure. Structure, 8, 471-479.

R. Blake Hill, Jae-Kyoung Hong, and William F. DeGrado. 2000. "Hydrogen bonded cluster can specify the native state of a protein". J. Am. Chem. Soc., 122, 46-747.

Lab Members

Graduate Students:
Marijke Koppenol
Jonathan Lees
Lora Picton
Frederick Tan
Robert Wells

Postdoctoral Fellow :

Frederick Tan

Lab Technician:
Jonathan Zuckerman