Biochemistry and Protein Structure
Office: Room 159
Lab: Rooms 152 and 154
Chemistry and Biochemistry Building
P.O. Box 173400
Bozeman, MT 59717
- B.A.: University of California at San Diego, Chemistry, 1985
- Ph.D.: Purdue University, West Lafayette, IN, Biochemistry/Biophysics 1993
- Postdoc.: Harvard Medical School and Howard Hughes Medical Institute, X-ray Crystallography 1994/1999
- BCH 380 GENERAL BIOCHEMISTRY
- BCH 545 ADVANCED PHYSICAL BIOCHEMISTRY
- BCH 550 PRINCIPLES OF STRUCTURE DETERMINATION BY X-RAY CRYSTALLOGRAPHY
Awards and Professional Activities
- 2007-Present: Editorial Board, Journal of Biological Chemistry
- 2009: Charles and Nora L. Wiley Award for Meritorious Research, Montana State University
- 2003-2006: Executive Board, Thermal Biology Institute, Montana State University
- 1998-1999: Armenise Postdoctoral Fellowship, Harvard Medical School
- 1994-1998: Postdoctoral Fellowship, Howard Hughes Medical Institute
- 1993: Outstanding Graduate Student, Department of Biological Sciences
- 1990-1993: Predoctoral Fellowship, American Heart Association
Lawrence Group Overview
Iron Transport and Iron Homeostasis
Iron plays an integral role in many biochemical processes essential to life. For example,
iron containing metalloproteins are necessary for the synthesis of DNA, respiration
and many key metabolic reactions. Thus, life as we know it is fully dependent on iron.
However, the same properties that allow iron to play a central role in the chemistry
of life, also lead to potentially deleterious effects. Specifically, excess Fe2+ combines
with naturally occurring peroxide to produce the hydroxyl radical, one of several
reactive oxygen species (ROS) that contribute to oxidative stress, reacting indiscriminately
with DNA, proteins and lipids. Hence, iron levels must be carefully balanced so that
enough iron is present to sustain key metabolic processes, but production of ROS are
minimized. To this end, an elaborate system of transport, storage and regulatory proteins
has evolved to effect iron homeostasis in humans and other organisms, including human
Importantly, disorders of iron metabolism are among the most prevalent diseases in humans. For example, iron deficiency is thought to affect more than one billion people worldwide, and is, particularly problematic in pregnant women and young children. In addition, the anemia of inflammation, a down regulation of iron levels in response to inflammation, is the most common form of anemia in hospitalized patients, and in patients with chronic diseases such as heart failure, rheumatoid arthritis, renal disease, and cancer. Similarly, inherited iron overload disorders, collectively known as hereditary hemochromatosis, are also common. For example, the occurrence of a single disease associated allele, HFEC282Y, is as high as 10% in individuals of Northern European descent, and is the most common autosomal recessive disease currently known. In homozygous individuals, progressive iron accumulation generates oxidative stress that results in significant cellular damage, inducing inflammation and fibrosis that eventuates in hepatic cirrhosis, hepatocellular carcinoma, diabetes mellitus, cardiac insufficiency and arthropathy. In addition, excess iron and/or oxidative stress is a factor in many neurodegenerative diseases, including Parkinsonâ€™s, Huntingtonâ€™s, Alzheimerâ€™s and ALS.
Consequently, the cellular machinery responsible for iron transport and homeostasis is worthy of significant investigation, and may provide potential targets for pharmacological intervention, to either promote or inhibit systemic or cellular iron uptake, or to interfere with iron acquisition in human pathogens, where iron availability is frequently the rate limiting nutrient. In this light, we are engaged in structural studies of both human and bacterial proteins involved in iron transport and homeostasis.
Maaty WS, Wiedenheft B, Tarlykov P, Schaff N, Heinemann J, Robison-Cox J, Valenzuela
J, Dougherty A, Blum P, Lawrence CM, Douglas T, Young MJ, Bothner B.:
Something old, something new, something borrowed; how the thermoacidophilic archaeon Sulfolobus solfataricus responds to oxidative stress
(2009) PLoS One. 16;4(9):e6964.
Gauss, G.H., Reott, M.A., Rocha, E.R., Young, M.J., Douglas, T., Smith, C.J. and Lawrence,
Characterization of the Bacteroides fragilis bfr gene product reveals a DPSL protein that suggests evolutionary links in the ferritin superfamily
Sendamarai, A. K., Ohgami, R. S., Fleming, M. D., and Lawrence, C. M.:
Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle.
Proceedings of the National Academy of Sciences of the United States of America (2008) 105, 7410-7415.
Gauss, G. H., Benas, P., Wiedenheft, B., Young, M., Douglas, T., and Lawrence, C.
Structure of the DPS-like protein from Sulfolobus solfataricus reveals a bacterioferritin-like dimetal binding site within a DPS-like dodecameric assembly.
Biochemistry (2006) 45, 10815-10827.
Ramsay, B., Wiedenheft, B., Allen, M., Gauss, G. H., Lawrence, C. M., Young, M., and
Douglas, T. :
Dps-like protein from the hyperthermophilic archaeon Pyrococcus furiosus.
Journal of Inorganic Biochemistry (2006) 100, 1061-1068.
Lawrence, C. M., Ray, S., Babyonyshev, M., Galluser, R., Borhani, D. W., and Harrison,
S. C. :
Crystal structure of the ectodomain of human transferrin receptor
Science (1999) 286, 779-782.
Archaeal Viruses and Virus-Host Interactions
The hyperthermophilic Crenarchaeal viruses show incredible morphological diversity. This is accompanied by extreme genetic diversity, wherein most viral genes lack significant similarity to genes of known function. The lack of sequence similarity to genes of known function has, in turn, complicated efforts to elucidate viral life cycles, virus-host relationships, and the underlying genetics and biochemistry. We postulate, however, that many of the genes in these viruses are not unique. Rather, their encoded proteins bear remote similarities to proteins with known functions, but these similarities are masked by evolution and adaptation to extremes of temperature and pH. In this light, tertiary (3D) structural similarities between proteins persist longer on the evolutionary time scale than either primary (amino acid) or genomic sequence (DNA) similarities. Thus, we are pursuing structural studies of crenarchaeal viral proteins in order to arrive at testable functional hypotheses. Our work over the last three years clearly demonstrates the validity of this approach; protein tertiary structure does suggest function. And the insights gained from our structural studies are suggesting functions for an ever increasing number of viral proteins. These structure-function relationships are relevant not only to the viruses under study (SSVs and STIV), but for the Crenarchaea in general.
Menon, S and Lawrence C.M. :
in Encyclopedia of Genetics, (2012)2nd Edition (Maloy, S. and Hughes, K., Eds.) Elsevier (In Press)
Heinemann J., Maaty W. S., Gauss G. H. , Akkaladevi N., Brumfield S. K., Rayaprolu
V., Young M.J., Lawrence C.M., Bothner B.:
Fossil record of an archaeal HK97-like provirus.
Virology (2011) 417, 362-368.
Lawrence, C. M., and White, M. F. :
Recognition of archaeal CRISPR RNA; no P in the alindromic repeat?
Structure (2011) 19, 142-4
Menon S.K., Eilers B.J., Young M.J., Lawrence C.M. :
The crystal structure of D212 from sulfolobus spindle-shaped virus ragged hills reveals a new member of the PD-(D/E)XK nuclease superfamily?
J Virol. (2010) 84(12):5890-7.
3D presentation of structural and image data.
J Biol Chem (2009) 284, 21101.
Fulton, J., Bothner, B., Lawrence, M., Johnson, J. E., Douglas, T., and Young, M.:
Genetics, biochemistry and structure of the archaeal virus STIV.
Biochemical Society Transactions (2009) 37, 114-117.
Lawrence, C. M., Menon, S., Eilers, B. J., Bothner, B., Khayat, R., Douglas, T., and
Young, M. J.:
Structural and functional studies of archaeal viruses
J Biol Chem. (2009) 284(19):12599-12603.
Menon, S. K., Maaty, W. S., Corn, G. J., Kwok, S. C., Eilers, B. J., Kraft, P., Gillitzer,
E., Young, M. J., Bothner, B., and Lawrence, C. M. :
Cysteine usage in Sulfolobus spindle-shaped virus 1 and extension to hyperthermophilic viruses in general.
Virology 376, 270-278.
Larson, E. T., Eilers, B., Menon, S., Reiter, D., Ortmann, A., Young, M. J., and Lawrence,
C. M. :
A winged-helix protein from suffiblobus turreted icosahedral virus points toward stabilizing disulfide bonds in the intracellular proteins of a hyperthermophilic virus
Virology (2007) 368, 249-261.
Larson, E. T., Eilers, B. J., Reiter, D., Ortmann, A. C., Young, M. J., and Lawrence,
A new DNA binding protein highly conserved in diverse crenarchaeal viruses
Virology (2007) 363, 387-396.
Khayat, R., Tang, L., Larson, E. T., Lawrence, C. M., Young, M., and Johnson, J. E.
Structure of an archaeal virus capsid protein reveals a common ancestry to eukaryotic and bacterial viruses.
Proceedings of the National Academy of Sciences of the United States of America (2005) 102, 18944-18949.
Kraft, P., Gauss, G. H., Young, M., and Lawrence, C. M. :
Structural Studies of Crenarchaeal Viral Proteins: Structure Suggests Function
in Geothermal Biology and Geochemistry in Yellowstone National Park (2005) (Inskeep, W. P., and McDermot, T. R., Eds.) pp 305-316, Montana State University, Bozeman.
Kraft, P., Oeckinghaus, A., Kummel, D., Gauss, G. H., Gilmore, J., Wiedenheft, B.,
Young, M., and Lawrence, C. M.:
Crystal structure of F-93 from Sulfolobus spindle-shaped virus 1, a winged-helix DNA binding protein.
Journal of Virology (2004) 78, 11544-11550.
Kraft, P., Kummel, D., Oeckinghaus, A., Gauss, G. H., Wiedenheft, B., Young, M., and
Lawrence, C. M. :
Structure of D-63 from sulfolobus spindle-shaped virus 1: Surface properties of the dimeric four-helix bundle suggest an adaptor protein function
Journal of Virology (2004) 78, 7438-7442.
Larson, E. T., Reiter, D., Young, M., and Lawrence, C. M. :
Structure of A197 from Sulfolobus turreted icosahedral virus: a crenarchaeal viral glycosyltransferase exhibiting the GT-A fold.
Journal of Virology (2006) 80, 7636-7644.