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   Soluble guanylate cyclase (sGC) is a nitric oxide (NO) sensing hemoprotein that has been described in eukaryotes from Drosophila to humans.   Genomic analysis has recently placed sGC within a larger family of heme proteins including prokaryotic proteins with significant homology (15-40% identity) to the heme domain of sGC (1).  We have begun to clone and characterize members of this new family of heme proteins and the key observation from initial studies (2) is that some members, those proteins from most eukaryotes and facultative aerobic prokaryotes, bind NO in a five-coordinate high-spin heme complex, but do not bind oxygen (O₂), the same ligand binding characteristics as sGC.  H-NOX family members from obligate aerobic prokaryotes, however, bind O₂ and NO in a six-coordinate low-spin heme complex, similar to the globins and other O₂-sensing heme proteins.  Thus we propose that these proteins are members of a family of hemoproteins that are related to the heme domain from sGC and are able to discriminate between NO and O₂.   We are calling this domain the H-NOX (Heme-Nitric Oxide and/or OXygen binding) domain.

   As all of the members of this family are either fused to or located in the same operon as signaling proteins we suggest this heme domain is, in fact, a heme sensor domain.  Two hypotheses thus arise and experiments directed at testing these possible signaling pathways are underway.

   Furthermore, as we have suggested that this family is able to use a homologous protein fold and an identical heme cofactor to discriminate between NO and O₂ binding, the question of how ligand discrimination takes place in the H-NOX family of heme proteins is raised.   In collaboration with the Kuriyan Lab, we have solved the crystal structure of the H-NOX domain from Thermoanaerobacter tengcongensis to 1.77 Å (3).

   This structure reveals that tyrosine 140 is hydrogen bonded to the bound oxygen, leading to the prediction that this is an important residue for ligand discrimination in this family, a hypothesis that is currently being tested (4).  For a current review on our work in this area, see reference 5.
 

References:

1. Iyer, L. M., Anantharaman, V., & Aravind, L. (2003) Ancient conserved domains shared by animal soluble guanylyl cyclases and bacterial signaling proteins, BMC Genomics 4, 5.


2. Karow, D. S., Pan, D., Tran, R., Pellicena, P., Presley, A., Mathies, R. A., & Marletta, M. A. (2004) Spectroscopic characterization of the soluble guanylate cyclase-like heme domains from Vibrio cholerae and Thermoanaerobacter tengcongensis, Biochemistry 43, 10203-10211.


3. Pellicena, P., Karow, D. S., Boon, E. M., Marletta, M. A., & Kuriyan, J. (2004) Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases, Proc. Natl. Acad. Sci. U. S. A. 101, 12854-12859.


4. Boon, E. M., Huang, S. H., & Marletta, M. A. (2005) A molecular basis for NO selectivity in soluble guanylate cyclase, Nature Chemical Biology, in press.


5. Boon, E. M., & Marletta, M. A. (2005) Ligand specificity of H-NOX domains: from sGC to bacterial NO sensors, J. Inorg. Biochem. 99, 892-902.