Robert Haselkorn, PhD
The Molecular Genetics of Nitrogen Fixation

Professor Emeritus, Molecular Genetics & Cell Biology, Biochemistry & Molecular Biology, Chemistry, Committee on Microbiology, Fanny L. Pritzker Distinguished Service Professor, Committee on Developmental Biology, Committee on Genetics

A.B., High honors in Chemistry, Princeton University, 1956
Ph.D., Biochemistry, Harvard University, 1959

 

Research Summary

Our current program is focused on two sets of problems: heterocyst differentiation in filamentous cyanobacteria and the properties of the enzyme acetyl-CoA carboxylase (ACC).

The cyanobacterium Anabaena grows in very long chains, the cells carrying out green plant photosynthesis. When faced with a shortage of fixed nitrogen, specialized cells called heterocysts differentiate at regular intervals along each filament, usually separated by about ten vegetative cells. The heterocysts do not divide. They quit doing carbon fixation but instead create an anaerobic environment for nitrogen fixation. The sequenced genome of Anabaena contains about 7000 genes, of which about 1500 are expressed differentially during heterocyst development. This program involves a cascade of transcription that involves at the start a factor called HetR, which we discovered long ago. This protein is studied now by many labs. One of my alumni identified the palindromic sequence in the genome to which it binds and another found a small peptide that prevents that binding. We have crystallized HetR from many species of cyanobacteria and solved the X-ray structure of one from the thermophile Fischerella. We have also solved the structure of complexes of the HetR dimer with several palindromic DNA sequences, ones containing 21, 23 and 25 base pairs. This work is continuing, in collaboration with Andrzej Joachimiak at the Argonne National Laboratory, Michelle Ye in China, and Sean Callahan in Hawaii. We also follow single heterocyst differentiation using confocal fluorescence microscopy. The current program is pursued by postdocs Shan Ke and Amin Nasser.

The program on ACC is directed by Research Associate Piotr Gornicki, who was the first to purify the two wheat isozymes (chloroplast and cytoplasmic) and to clone their genes. We used their respective cDNAs in recombinant yeast to study the basis of herbicide sensitivity and found a single amino acid responsible for the resistance phenotype. The recombinant yeast system was then exploited to study the ACCs of parasites and eventually the two isoforms of human ACC. Currently the lab is working on the human enzymes to determine possible targets for drugs to treat obesity.


Selected Publications

Youngchang Kim, Grazyna Joachimiak, Zi Ye, T. Andrew Binkowski, Rongguang Zhang, Piotr Gornicki, Sean M. Callahan, Wolfgang R. Hess, Robert Haselkorn and Andrzej Joachimiak. Structure of the Transcription Factor HetR Required for Heterocyst Differentiation in Cyanobacteria. Proc. Natl Acad. Sci USA 108: 10109-10114 (2011). (PubMed)

J. Marjanovic, D. Chalupska, C. Patenode, A. Coster, E. Arnold, A. Ye, G. Anesi, R.Y.Lu, I. Okun, S. Tkachenko, R. Haselkorn and P. Gornicki. A recombinant yeast screen for new inhibitors of human ACC2 identifies potential drugs to treat obesity. Proc. Nat. Acad. Sci. USA 107: 9093-9098 (2010). (PubMed)

Liu, W., Harrison, D.K., Chalupska, D., Gornicki, P., O’Donnell, C.C., Adkins, S.W., Haselkorn, R. and Williams, R.R. Single-site mutations in the carboxyltransferase domain of plastid acetyl-CoA carboxylase confer resistance to grass-specific herbicides. Proc. Natl Acad Sci. USA 104: 3627-3632 (2007). (PubMed)

Rouhaiainen,L., Vakkilainen, T., Siemer, B.L., Buikema, W., Haselkorn, R., and Sivonen, K. Genes coding for the synthesis of hepatotoxic heptapeptides (Microcystins) in the cyanobacterium Anabaena strain 90. App. Env. Micro. 70: 686-692 (2004). (PubMed)

 

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