title: Analysis of inter-residue contacts reveals folding stabilizers in P-loops of potassium, sodium, and TRPV channels.
abstract: The family of P-loop channels includes potassium, sodium, calcium, cyclic nucleotide-gated and TRPV channels, as well as ionotropic glutamate receptors. Despite vastly different physiological and pharmacological properties, the channels have structurally conserved folding of the pore domain. Furthermore, crystallographic data demonstrate surprisingly similar mutual disposition of transmembrane and membrane-diving helices. To understand determinants of this conservation, here we have compared available high-resolution structures of sodium, potassium, and TRPV1 channels. We found that some residues, which are in matching positions of the sequence alignment, occur in different positions in the 3D alignment. Surprisingly, we found 3D mismatches in well-packed P-helices. Analysis of energetics of individual residues in Monte Carlo minimized structures revealed cyclic patterns of energetically favorable inter- and intra-subunit contacts of P-helices with S6 helices. The inter-subunit contacts are rather conserved in all the channels, whereas the intra-subunit contacts are specific for particular types of the channels. Our results suggest that these residue-residue contacts contribute to the folding stabilization. Analysis of such contacts is important for structural and phylogenetic studies of homologous proteins.
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Thorez Prospect, St. Petersburg, 194223, Russian Federation.
authors.forename: V S
authors.initials: VS
authors.lastname: Korkosh
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Thorez Prospect, St. Petersburg, 194223, Russian Federation.|Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ONT, Canada.
authors.forename: B S
authors.initials: BS
authors.lastname: Zhorov
authors.affiliation: Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 44 Thorez Prospect, St. Petersburg, 194223, Russian Federation. denistikhonov2002@yahoo.com.
authors.forename: D B
authors.initials: DB
authors.lastname: Tikhonov
mesh_terms: D000595:Amino Acid Sequence; D008958:Models, Molecular; D009010:Monte Carlo Method; D015221:Potassium Channels / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D015222:Sodium Channels / Q000737:chemistry*; D050916:TRPV Cation Channels / Q000737:chemistry*
chemical_list: D015221:Potassium Channels; D015222:Sodium Channels; D050916:TRPV Cation Channels
keywords: Homology modeling; Monte Carlo energy minimization; Protein folding