Molecular mechanisms of cellular signaling and biomolecular recognition using Nuclear magnetic resonance spectroscopy (NMR), biophysical chemistry and molecular biology. Current interests include molecular mechanisms of zinc finger transcription factor functions governing divalent zinc homeostasis and brain development in eukaryotic organisms, and collaborative structure/function studies involving several areas of bacterial pathogenesis.

NMR is a well-suited technique to investigate structural and dynamic changes of proteins in solution. As the home of the School of Biological Sciences (SBS) NMR Facility, we are using NMR and other biophysical and molecular biology approaches to explore several aspects of zinc finger transcription factor biology.  A major focus of the lab is to characterize the molecular mechanisms that control divalent zinc [Zn(II)] homeostasis in yeast and mammalian cells. All known organisms require Zn(II), and yet this essential nutrient is toxic if accumulated to excess. Zn(II) homeostasis in mammalian and yeast cells is regulated at least in part at the level of coordination chemistry by two zinc finger proteins, Zap1 (yeast) and MTF-1 (mammalian). MTF-1 and Zap1 are transcription factors that control the expression of proteins to transport Zn(II) in or out of the cellular compartments [Zn(II) transport proteins] or to sequester Zn(II) through high-affinity metal-ligand coordination (metallothioneins). Studies on MTF-1 involve a close collaboration with Dr. Glen Andrews at the neighboring University of Kansas Medical Center, Department of Molecular Biology and Biochemistry.

A new area of focus in the lab centers on understanding the molecular mechanisms whereby a special group of zinc finger-containing Zic family transcription factors regulate key processes that are essential for human brain development. These studies are ongoing in close collaboration with Dr. Gerald Wyckoff in the SBS.

In two additional collaborative projects, we are exploring the molecular mechanisms of targeted elements of bacterial pathogenesis. We are currently collaborating with Dr. Lawrence Dreyfus, Dean of the UMKC, SBS to explore the structure/function relationships that underlie the cytotoxic effects of the cytolethal distending toxin. In a second collaboration with Dr. Brian Geisbrecht  (SBS), we are investigating structural and dynamic aspects of antigen/receptor interactions.

We acknowledge current and prior funding for these projects from The National Institutes of Health and the University of Missouri Research Board.

Y. Li, T. Kimura, R.W. Huyck, J.H. Laity, G.K. Andrews (2008) "Zinc-induced formation of a co-activator complex containing the zinc-sensing transcription factor MTF-1, CBP/p300 and Sp1" Mol. Cell. Biol. 28 (13) p.4275-4284. Epub. May 5, 2008.

R. Stoll, B.M. Lee, E.W. Debler, J.H. Laity, I.A. Wilson, H.J. Dyson and P.E. Wright. (2007) "Structure of the Wilms Tumor Suppressor Protein Zinc Finger Domain Bound to DNA", J. Mol. Biol. 372(5), p.1227-45.

J.H. Laity and G.K. Andrews. (2007) "Understanding the Mechanisms of Zinc-Sensing by metal-response element binding transcription factor-1(MTF-1)", Arch. Biochem. Biophys. 463(2), p. 201-210.

Z. Wang, B.M. Potter, A.M. Gray, K.A. Sacksteder, B.V. Geisbrecht and J.H. Laity.(2007) "The Solution Structure of Antigen MPT64 from Mycobacterium tuberculosis Defines a New Family of Beta-Grasp Proteins", J. Mol. Biol. 366 (2), p375-381.

J.S. Hontz, M.T. Villar-Lecumberri, B.M. Potter, M.D. Yoder, L.A. Dreyfus and J.H. Laity (2006) "Differences in crystal and solution structures of the cytolethal distending toxin B subunit: relevance to nuclear translocation and functional activation", J. Biol. Chem., 281 (35), p25365-25372. PDF available here.

Y. Li, T. Kimura, J.H. Laity and G.K. Andrews (2006) "The zinc-sensing mechanism of mouse MTF-1 involves linker peptides between the zinc fingers", Mol. Cell Biol., 26(15), p5580-5587. Reprint available here.

Z. Wang, L.S. Feng, V. Matskevich,  K. Venkataraman, P. Parasuram and J.H. Laity (2006) "Solution Structure of a Zap1 Zinc-Responsive Domain Provides Insights into Metalloregulatory Transcriptional Repression in Saccharomyces cerevisiae", J. Mol. Biol., 357 (4), p1167-1183. PDF available here.

M.T. Villar-Lecumberri, B. M. Potter, Z. Wang, L.A. Dreyfus and J. H. Laity (2006) "NMR assignment of the E.coli-II cytolethal distending toxin CdtB subunit", J. Biomol. NMR., (34). Published online Feb.2, 2006. Supplementary material available here.

B.M. Potter, L.S. Feng, P. Parasuram, V.A. Matskevich, J.A. Wilson, G.K. Andrews and J.H. Laity (2005) "The Six Zinc Fingers of Metal-responsive Element Binding Transcription Factor-1 Form Stable and Quasi-ordered Structures with Relatively Small Differences in Zinc Affinities", J. Biol. Chem., 280, p28529 - 28540.

B.M. Potter, N.A. Knudsen, L.S. Feng, V.A. Matskevich, J.A. Wilson, G.K. Andrews and J.H. Laity (2005) "NMR assignment of the six zinc fingers of MTF-1 in the free and DNA bound states", J. Biomol. NMR., 32, p94. Supplementary material available here.

J.M. Danahy, B.M. Potter, B.V. Geisbrecht and J.H. Laity (2005) "NMR Assignment of Protein Rv1980c from Mycobacterium tuberculosis", J. Biomol. NMR., 33, p73. Supplementary material available here.

J.H. Laity (2004) "Cys2-His2 Zinc Finger Proteins", in Handbook of Metalloproteins, ed. A. Messerschmidt, 3rd ed., John Wiley & Sons Press, West Sussex, United Kingdom

J.H. Laity, B.M. Lee and P.E. Wright (2001) "Zinc Finger Proteins: New Insights into Structural And Functional Diversity". Curr. Opin. Struct. Biol., 11(1), p. 39-46.