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PEDS Advance Access first published online on April 5, 2004
This version published online on April 6, 2004
Protein Engineering Design and Selection, doi:10.1093/protein/gzh031
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Received December 15, 2003
Revised February 23, 2004
Accepted March 22, 2004
Oxford University Press 1741-0134

Article

How does a topological inversion change the evolutionary constraints on membrane proteins?

Hisako Ichihara 1, Hiromi Daiyasu 1, and Hiroyuki Toh 1*

1 Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan; Biomolecular Engineering Research Institute, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan

* To whom correspondence should be addressed. E-mail: toh{at}kuicr.kyoto-u.ac.jp.


  Abstract

The members of the aquaporin family and those of the ClC chloride ion channel family consist of two-fold tandem repeats. The orientation of the N-terminal domain against membrane is opposite to that of the C-terminal domain. Several lines of evidence suggest that the extracellular and the cytoplasmic environments impose different evolutionary constraints on proteins (e.g. positive-inside rule). Therefore, the different constraints would affect the corresponding regions of the two domains, which are exposed to the different environments. To examine this hypothesis, the N- and the C-terminal domains were aligned, and the difference in residue composition or conservation pattern between the two domains was calculated at each alignment site by several methods. Then, the residues corresponding to the sites exhibiting significant difference were mapped onto the tertiary structure. In spite of the difference of the methods, the mapped residues clustered on the pore surface of the channel; in contrast, the number of the residues mapped on the extracellular or cytoplasmic sides of the proteins was quite small. A minor modification of the methods improved the sensitivity to detect sites related to the positive-inside rule. The results support our hypothesis about the relationship between the topological inversion and the different constraints.

Keywords: Membrane Protein / Molecular Evolution / Positive-inside rule / Topology


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