engleski

Homology of cation channel pore domains

Difficulty in detecting homology for membrane proteins has been acknowledged for a long time in database searches. The membrane environment restricts the physical-chemical attributes of amino acids and leads to high similarity of helical transmembrane domains (TMH). For 2TMH+P, the pore forming domain of cation channels, membrane-dipped region is up to the 66% of the domain. The conserved fold proposed on the basis of primary sequence and/or topological similarity has been disputed with experiments suggesting different pore arrangements in different families. To investigate the conservation of this fold on the secondary structure level, we constructed the unique database of the superfamily 2TMH+P domains, which was then subdivided into K+ channel domains and other. The identity between K+ channel and all other domains is less than 25% indicating that although the similarity is high, it might not be significant enough to conclude that homology exists. We used membrane-associated secondary structure conformational parameters [1] from K+ channel domains for the detection of pores. The correlation of maximums in our conformational profiles with positions of secondary structure elements in K+ channels has shown that TMH preferences and hydrophobic moments are good descriptors of the K+ channel secondary structure arrangements. The precise locations of these structural elements were determined by homology modeling with the Kcsa 3D structure. We were than able to use the same conformational parameters to infer pore domain fold conservation in non K+ channels. Most of 2TMH+P domains in these channels were detected (87%) by our algorithm. The specificity of the method was tested on the database of 354 nonhomologous membrane proteins devoid of cationic channels. There were 11% false positive hits, but some of them were found in ion transporters suspected to contain the 2TMH+P domain. We also investigated the exon/intron boundaries in gene parts coding for these domains. The tendency to find the whole 2TMH+P foldon in the single exon has been noted for various evolutionary distant channels. [1] Juretić, D. et al. Theoretical and Computational Chemistry, Vol.5. 405-445 ; Parkany C., Elsevier Science, Amsterdam, 1998.

homology; cation channel; pore domains

nije evidentirano