title: A novel dimerization interface of cyclic nucleotide binding domain, which is disrupted in presence of cAMP: implications for CNG channels gating.
abstract: Cyclic nucleotide binding domain (CNBD) is a ubiquitous domain of effector proteins involved in signalling cascades of prokaryota and eukaryota. CNBD activation by cyclic nucleotide monophosphate (cNMP) is studied well in the case of several proteins. However, this knowledge is hardly applicable to cNMP-modulated cation channels. Despite the availability of CNBD crystal structures of bacterial cyclic nucleotide-gated (CNG) and mammalian hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels in presence and absence of the cNMP, the full understanding of CNBD conformational changes during activation is lacking. Here, we describe a novel CNBD dimerization interface found in crystal structures of bacterial CNG channel MlotiK1 and mammalian cAMP-activated guanine nucleotide-exchange factor Epac2. Molecular dynamics simulations show that the found interface is stable on the studied timescale of 100 ns, in contrast to the dimerization interface, reported previously. Comparisons with cN-bound structures of CNBD show that the dimerization is incompatible with cAMP binding. Thus, the cAMP-dependent monomerization of CNBD may be an alternative mechanism of the cAMP sensing. Based on these findings, we propose a model of the bacterial CNG channel modulation by cAMP.
authors.affiliation: Institut de Biologie Structurale Jean-Pierre Ebel, Université Joseph Fourier - Grenoble 1, Grenoble, France.
authors.forename: Ivan Y
authors.initials: IY
authors.lastname: Gushchin
authors.forename: Valentin I
authors.initials: VI
authors.lastname: Gordeliy
authors.forename: Sergei
authors.initials: S
authors.lastname: Grudinin
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000242:Cyclic AMP / Q000378:metabolism*; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000737:chemistry* / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism; D015640:Ion Channel Gating; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary
chemical_list: D000596:Amino Acids; D054815:Cyclic Nucleotide-Gated Cation Channels; D020662:Guanine Nucleotide Exchange Factors; D000242:Cyclic AMP