We are interested in identifying disease-related changes to proteins, including expression levels, and conformational and post-translational modifications. We then develop small molecules to ameliorate these protein modifications.
Protein post-translational modification underlies most biological processes. Moreover, the dysregulation of protein modification plays a causative role in a number of disease states. Our laboratory studies protein modifications that occur during neurodegeneration, and tries to understand the role of modification in disease progression. We use high resolution, Fourier Transform Mass Spectrometry (FTMS), and are equipped for both electrospray and MALDI ionization, including MALDI mass spectral imaging of tissues.
"Modular Organization and Identification of a Mononuclear Iron Binding Site Within the NifU Protein", J. N. Agar, P. Yuvaniyama, R. F. Jack, V. L. Cash, A. D. Smith, D. R. Dean and M. K. Johnson, J. Biol. Inorg. Chem. 5, 167 177 (2000).
"NifS-directed Assembly of a Transient [2Fe-2S] Cluster in the NifU Protein", P. Yuvaniyama, J. N. Agar, V. L. Cash., M. K. Johnson, and D. R. Dean, Proc. Natl. Acad. Sci. USA 97, 599-604 (2000).
"Role of the IscU Protein in Iron-Sulfur Cluster Biosynthesis: IscS Mediated Assembly of a [Fe2S2] Cluster in IscU", J. N. Agar, L. Zheng, V. L. Cash, D. R. Dean, and M. K. Johnson, J. Am. Chem. Soc. 122, 2136 2137 (2000).
"IscU as a Scaffold for Iron Sulfur Cluster Biosynthesis: Sequential Assembly of [2Fe 2S] and [4Fe 4S] Clusters in IscU", J. N. Agar, C. Krebs, J. Frazzon, B. H. Huynh, D. R. Dean, and M. K. Johnson, Biochemistry (Accelerated Publication) 39, 7856 7862 (2000).
"Characterization of the NifU and NifS Fe-S cluster formation proteins essential for viability in Helicobacter pylori", J. W. Olson, J. N. Agar, M. K. Johnson, and R. Maier, Biochemistry 39, 16213-16219 (2000).
"Sulfur Transfer from IscS to IscU: The First Step in Iron-Sulfur Cluster Biosynthesis, A. D. Smith, J. N. Agar, K. A. Johnson, J. Frazzon, I. J. Amster, D. R. Dean, and M. K. Johnson, J. Am. Chem. Soc. 123, 11103-11104 (2001).
"IscA, an Alternate Scaffold for Fe-S cluster biosynthesis", C. Krebs, J. N. Agar, J. Frazzon, B. H. Huynh, D. R. Dean, and M. K. Johnson, Biochemistry, 40, 11069-14080 (2001).
"Biological Iron-Sulfur Cluster Assembly", J. N. Agar, D. R., Dean, M. K. Johnson, in Biochemistry and Physiology of Anaerobic Bacteria , L. G. Ljungdahl, M. W. W. Adams, L. L. Barton, J. G. Ferry, and M.K. Johnson eds., Springer-Verlag, 46-66 (2003).
"Relevance of oxidative injury in the pathogenesis of motor neuron diseases", J. N. Agar, H. D. Durham, Amyotroph Lateral. Scler. Other Motor Neuron Disord. 4, 232-42 (2003).
"Mutations in COX10 Result in a Defect in Mitochondrial Heme A Biosynthesis and Account for Multiple, Early Onset Clinical Phenotypes Associated With Isolated COX Deficiency", Antonicka H., Leary S. C., Guercin G, Agar J. N., Horvath R., Kennaway N. G., Harding, C. O., Jaksch M., Shoubridge E. A., Human Molecular Genetics, 12, 2693-2702 (2003).
"Overexpression of Metallothionein Protects Cultured Motor Neurons Against Oxidative Stress, but not Mutant Cu/Zn-Superoxide Dismutase Toxicity", D. M. Taylor, S. Minotti, J. N. Agar, H. D. Durham, Neurotoxicology, 25, 779-792 (2004).
"Focal Dysfunction of the Proteasome: A Pathogenic Factor in a Mouse Model of Amyotrophic Lateral Sclerosis", E. M. Kabashi and J. N. Agar (coauthors), D. M. Taylor, S. Minotti, H. D. Durham, Journal of Neurochemistry, 89, 1325-1335. (2004)
"Proteasome Activity or Expression is Not Altered by Activation of Heat Shock Transcription Factor HSF1 in Cultured Fibroblast and Myoblasts", D. M. Taylor, E. Kabashi, J. N. Agar, S. Minnoti, H. D. Durham., Cell Stress and Chaperones,10:230-41 (2005).
"NifS-mediated assembly of [4Fe-4S] clusters in the N- and C-terminal domains of the NifU scaffold protein", Smith AD, Jameson GN, Dos Santos PC, Agar JN, Naik S, Krebs C, Frazzon J, Dean DR, Huynh BH, Johnson MK. Biochemistry. 2005 Oct 4;44(39):12955-69.
"Tryptophan 32 potentiates aggregation and cytotoxicity of a copper/zinc superoxide dismutase mutant associated with familial amyotrophic lateral sclerosis", Taylor DM, Gibbs BF, Kabashi E, Minotti S, Durham HD, Agar JN. J Biol Chem. 2007 Jun 1;282(22):16329-35.
"Matrix solution fixation: histology-compatible tissue preparation for MALDI mass spectrometry imaging". Agar NY, Yang HW, Carroll RS, Black PM, Agar JN. Anal Chem. 2007 Oct 1;79(19):7416-23.
"Fitting neurological protein aggregation kinetic data via a 2-step, minimal/"Ockham's razor" model: the Finke-Watzky mechanism of nucleation followed by autocatalytic surface growth". Morris AM, Watzky MA, Agar JN, Finke RG. Biochemistry. 2008 Feb 26; 47(8):2413-27.
"Proteasomes remain intact, but show early focal alteration in their composition in a mouse model of amyotrophic lateral sclerosis". Kabashi E, Agar JN, Hong Y, Taylor DM, Minotti S, Figlewicz DA, Durham HD.J Neurochem. 2008 Apr 1
"Protein aggregation and protein instability govern familial amyotrophic lateral sclerosis patient survival". Wang Q, Johnson JL, Agar NY, Agar JN. PLoS Biol. 2008 Jul 29;6(7):e170.
"A hierarchical algorithm for calculating the isotopic fine structures of molecules". Li L, Kresh JA, Karabacak NM, Cobb JS, Agar JN, Hong P. J Am Soc Mass Spectrom. 2008 Dec;19(12):1867-74.
"Sensitive and specific identification of wild type and variant proteins from 8 to 669 kDa using top-down mass spectrometry". Karabacak NM, Li L, Tiwari A, Hayward LJ, Hong P, Easterling ML, Agar JN. Mol Cell Proteomics. 2009 Apr;8(4):846-56.
"A common property of amyotrophic lateral sclerosis-associated variants: destabilization of the copper/zinc superoxide dismutase electrostatic loop". Molnar KS, Karabacak NM, Johnson JL, Wang Q, Tiwari A, Hayward LJ, Coales SJ, Hamuro Y, Agar JN. J Biol Chem. 2009 Nov 6;284(45):30965-73.
"Transformative Effects of Higher Magnetic Field in Fourier Transform Ion Cyclotron Resonance Mass Spectrometry". Karabacak NM, Easterling ML, Agar NY, Agar JN. J Am Soc Mass Spectrom. 2010 Mar 31.
"Imaging of meningioma progression by matrix-assisted laser desorption ionization time-of-flight mass spectrometry". Agar NY, Malcolm JG, Mohan V, Yang HW, Johnson MD, Tannenbaum A, Agar JN, Black PM. Anal Chem. 2010 Apr 1;82(7):2621-5.
"Structural characterization of intact proteins is enhanced by prevalent fragmentation pathways rarely observed for peptides". Cobb JS, Easterling ML, Agar JN. J Am Soc Mass Spectrom. 2010 Jun;21(6):949-59.
"Memory Efficient Calculation of the Mass States of a Molecule Rapid Communications in Mass Spectrometry". L. Li., N. M. Karabacak, J. N. Agar. June 14 2010.
"Strategies for stabilizing superoxide dismutase (SOD1), the protein destabilized in the most common form of familial amyotrophic lateral sclerosis". Auclair JR, Boggio KJ, Petsko GA, Ringe D, Agar JN. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21394-9.
"Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS". Bosco DA, Morfini G, Karabacak NM, Song Y, Gros-Louis F, Pasinelli P, Goolsby H, Fontaine BA, Lemay N, McKenna-Yasek D, Frosch MP, Agar JN, Julien JP, Brady ST, Brown RH Jr. Nat Neurosci. 2010 Nov;13(11):1396-403.
"Evidence of the participation of remote residues in the catalytic activity of Co-type nitrile hydratase from Pseudomonas putida". Brodkin HR, Novak WR, Milne AC, D'Aquino JA, Karabacak NM, Goldberg IG, Agar JN, Payne MS, Petsko GA, Ondrechen MJ, Ringe D. Biochemistry. 2011 Jun 7;50(22):4923-35. Epub 2011 May 12.
Last review: August 8, 2011