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PEDS Advance Access originally published online on June 30, 2006
Protein Engineering Design and Selection 2006 19(9):409-419; doi:10.1093/protein/gzl025
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

A novel mechanism of allosteric regulation of archaeal phosphoenolpyruvate carboxylase: a combined approach to structure-based alignment and model assessment

Hiroyoshi Matsumura1,2, Katsura Izui3 and Kenji Mizuguchi1,4,5

1 Department of Biochemistry, University of Cambridge Tennis Court Road, Cambridge CB2 1GA, UK 2 Department of Applied Chemistry, Graduate School of Engineering, Osaka University Suita, Osaka 565-0871, Japan 3 Department of Biotechnological Science, Kinki University Kinokawa, Wakayama 649-6493, Japan 4 Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge Wilberforce Road, Cambridge CB3 OWA, UK

5To whom correspondence should be addressed. E-mail: kenji{at}cryst.bioc.cam.ac.uk

Phosphoenolpyruvate carboxylase (PEPC) catalyzes the irreversible carboxylation of phosphoenolpyruvate (PEP) and plays a crucial role in fixing atmospheric CO2 in C4 and CAM plants. The enzyme is widespread in plants and bacteria and mostly regulated allosterically by both positive and negative effectors. Archaeal PEPCs (A-PEPCs) have unique characteristics in allosteric regulation and molecular mass, distinct from their bacterial and eukaryote homologues, and their amino acid sequences have become available only recently. In this paper, we generated a structure-based alignment of archaeal, bacterial and eukaryote PEPCs and built comparative models using a combination of fold recognition, sequence and structural analysis tools. Our comparative modeling analysis identified A-PEPC-specific strong interactions between the two loops involved in both allostery and catalysis, which explained why A-PEPC is not influenced by any allosteric activators. We also found that the side-chain located three residues before the C-terminus appears to play a key role in determining the sensitivity to allosteric inhibitors. In addition to these unique features, we revealed how archaeal, bacterial and eukaryote PEPCs would share a common catalytic mechanism and adopt a similar mode of tetramer formation, despite their divergent sequences. Our novel observations will help design more efficient molecules for ecological and industrial use.

Keywords: allosteric regulation/carboxylase/CO2 fixation/homology recognition/sequence alignment

Received April 17, 2006; revised May 23, 2006; accepted May 30, 2006.


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