Chemical-Biology Interface Faculty
Program in Molecular Biophysics Faculty
Institute for NanoBioTechnology Faculty
20B Mudd Hall
Department of Biology
Johns Hopkins University
3400 N. Charles Street
Baltimore, MD 21218-2685
Office 410 516-6783
Lab 410 516-6790
Departmental fax 410 516-5213
PostdoctoralUniversity of Pennsylvania
What is the molecular basis of mitochondrial homeostasis?
The Hill Laboratory is an interdisciplinary team seeking to understand the fundamental
events that regulate mitochondrial homeostasis. Our goal is to determine how
proteins interact with other
macromolecules to control these basic membrane fission and fusion processes in healthy
and dying cells. We strive to understand these interactions on a physicochemical
level, with an eye for gleaning universal principles of protein chemistry including
interactions with membrane bilayers that are fundamental to a wide variety of cellular
processes. Given that defects in mitochondrial fission and fusion cause severe
neuropathies, cardiomyopathies, and even death, we expect our findings to identify
new therapeutic avenues.
A key feature of some proteins that affect mitochondrial homeostasis is the structural transformation from soluble to membrane-bound conformations, a phenomenon referred to as amphitropism. Associating with, or dissociating from, a membrane (i.e. amphitropism) has significant functional consequences for numerous biological processes: it can affect enzymatic activity (CCT, PLC), can promote changes in organelle and cell morphology (minD, dynamins), or can act as a regulatory switch in various signaling cascades (PKC, ESCRTs). However, neither what drives proteins to reversibly interact with membranes nor how this function controls biological outcomes are clearly understood. These interactions are likely governed by evolutionarily conserved mechanisms that are still poorly understood and is one focus of our efforts.
Towards these goals, we use a wide range of tools including genetic, cell biological, biochemical, and biophysical methods including NMR spectroscopy and x-ray crystallography for protein structure determination. Please visit our lab website for more information: https://sites.google.com/site/hillbiologylab/
Selected PublicationsJ.E. Tooley, V. Khangulov, J.P. Lees, J.L. Schlessman, M.C. Bewley, A. Héroux, J. Bosch*, and R.B. Hill*, 1.75 Å crystal structure of fission protein Fis1 from Saccharomyces cerevisiae reveals elusive interactions of the autoinhibitory domain, Acta Cryst (2011) F67, 1310–1315.
R.C. Wells and R.B. Hill, The Fis1 cytosolic domain binds and reversibly clusters lipid vesicles, PLoS-1, (2011) 6, e21384, doi:10137/journalpone0021384.
D.V. Jeyaraju, H.M. McBride, R.B. Hill*, L. Pellegrini*, Structural and mechanistic basis of Parl activity and regulation, Cell Death Differ., (2011) 18, 1531-9.
F.J. Tan, F.J., J.E. Zuckerman, R.C. Wells, R.B. Hill, The C. elegans B-cell lymphoma 2 (bcl-2) homolog Cell death abnormal 9 (CED-9) associates with and remodels lipid membranes, Prot. Sci. (2011) 20, 62-74.
C.R. Chang†, C.M. Manlandro†, D. Arnoult, J. Stadler, A.E. Posey, R.B. Hill*, and C. Blackstone*, A lethal de novo mutation in the middle domain of the dynamin-related GTPase Drp1 impairs higher-order assembly and mitochondrial division, J. Biol. Chem. (2010) 285, 32494-503. PMCID: PMC2952251.
R.B. Hill and L. Pellegrini, The PARL family of mitochondrial rhomboid proteases. Semin Cell Dev Biol. (2010) 21,582-92. PMCID: PMC2908206
L.K. Picton†, S. Casares†, A.C. Monahan, A. Majumdar, & R.B. Hill, Evidence for conformational heterogeneity of fission protein Fis1 from S. cerevisiae, Biochemistry (2009) 21, 6598-609. PMCID: PMC2785846
F.J. Tan, M. Husain, C.M. Manlandro, M. Koppenol, A.Z. Fire, & R.B. Hill, CED-9 and mitochondrial homeostasis in C. elegans muscle., J. Cell Sci. (2008) 102, 3373-82. PMCID: PMC2785848
R.C. Wells, L.K. Picton, S.C.P. Williams, F.J. Tan, and R.B. Hill, Direct binding of the dynamin-like GTPase, Dnm1, to mitochondrial dynamics protein Fis1 is negatively regulated by the Fis1 N-terminal arm., J. Biol. Chem. (2007) 282, 33769-75.
F.J. Tan, J.E. Zuckerman, A.Z. Fire, and R.B. Hill, Regulation of apoptosis by C. elegans CED-9 in the absence of the C-terminal transmembrane domain, Cell Death Differ. (2007) 14, 1925-35.
G.R. Thuduppathy, O. Terrones, J. W. Craig, G. Basañez, and R.B. Hill, The N-terminal domain of Bcl-xL reversibly binds membranes in a pH-dependent manner, Biochemistry (2006) 45, 14533-42. PMCID: PMC1764622
G.R. Thuduppathy, J. W. Craig, V. Kholodenko, A. Schon, and R.B. Hill, Evidence that membrane insertion of the cytosolic domain of Bcl-xL might be governed by an electrostatic mechanism, J. Mol. Biol., (2006) 359, 1045-58. PMCID: PMC1785297
G.R. Thuduppathy and R.B. Hill, Acid destabilization of the solution conformation of Bcl-xL does not drive its pH-dependent insertion into membranes, Protein Sci, (2006) 15, 248-57. PMCID: PMC1752203
Y. Fannjiang, W.C. Cheng, S.J. Lee, B. Qi, J. Pevsner, J.M. McCaffery, R.B. Hill, G. Basañez, and J.M. Hardwick, Mitochondrial fission proteins regulate programmed cell death in yeast., Genes Dev., (2004) 18, 2785-97. PMCID: PMC528898
G.R. Thuduppathy and R.B. Hill, Applications of NMR Spin Relaxation Methods for Measuring Biological Motions, Methods Enzymol., (2004) 384, 243-64.
J.A. Dohm, S.J. Lee, J.M. Hardwick, R.B. Hill*, and A.G. Gittis*, The cytosolic domain of the human mitochondrial fission protein Fis1 adopts a TPR fold, Proteins (2004) 54, 153-6.
†co-first authors *co-corresponding authors