title: Potential cation and H+ binding sites in acid sensing ion channel-1.
abstract: Acid sensing ion channels (ASICs) are cation-selective membrane channels activated by H(+) binding upon decrease in extracellular pH. It is known that Ca(2+) plays an important modulatory role in ASIC gating, competing with the ligand (H(+)) for its binding site(s). However, the H(+) or Ca(2+) binding sites involved in gating and the gating mechanism are not fully known. We carried out a computational study to investigate potential cation and H(+) binding sites for ASIC1 via all-atom molecular dynamics simulations on five systems. The systems were designed to test the candidacy of some acid sensing residues proposed from experiment and to determine yet unknown ligand binding sites. The ion binding patterns reveal sites of cation (Na(+) and Ca(2+)) localization where they may compete with protons and influence channel gating. The highest incidence of Ca(2+) and Na(+) binding is observed at a highly acidic pocket on the protein surface. Also, Na(+) ions fill in an inner chamber that contains a ring of acidic residues and that is near the channel entrance; this site could possibly be a temporary reservoir involved in ion permeation. Some acidic residues were observed to orient and move significantly close together to bind Ca(2+), indicating the structural consequences of Ca(2+) release from these sites. Local structural changes in the protein due to cation binding or ligand binding (protonation) are examined at the binding sites and discussed. This study provides structural and dynamic details to test hypotheses for the role of Ca(2+) and Na(+) ions in the channel gating mechanism.
authors.affiliation: Department of Biochemistry, Center for Biophysics and Computational Biology, Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: Saher Afshan
authors.initials: SA
authors.lastname: Shaikh
authors.forename: Emad
authors.initials: E
authors.lastname: Tajkhorshid
mesh_terms: D062565:Acid Sensing Ion Channels; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002645:Chickens; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011522:Protons; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D011522:Protons; D015222:Sodium Channels; D002118:Calcium
references.citation: Nature. 2007 Sep 20;449(7160):316-23
references.pmid: 17882215
references.citation: Neuron. 2003 Jan 9;37(1):75-84
references.pmid: 12526774
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: J Biol Chem. 2008 Jan 4;283(1):572-581
references.pmid: 17981796
references.citation: Neuroscience. 1980;5(12):2325-7
references.pmid: 6970348
references.citation: Neurosci Lett. 2007 Oct 9;426(1):12-7
references.pmid: 17881127
references.citation: J Gen Physiol. 2002 Oct;120(4):553-66
references.pmid: 12356856
references.citation: Curr Opin Neurobiol. 1998 Jun;8(3):418-24
references.pmid: 9687356
references.citation: Physiol Rev. 2002 Jul;82(3):735-67
references.pmid: 12087134
references.citation: Nature. 1997 Mar 13;386(6621):173-7
references.pmid: 9062189
references.citation: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references.pmid: 8744570
references.citation: J Comput Chem. 2004 Aug;25(11):1400-15
references.pmid: 15185334
references.citation: J Biol Chem. 2004 Mar 19;279(12):11006-15
references.pmid: 14701823
references.citation: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references.pmid: 24889800
references.citation: Nat Neurosci. 2001 Sep;4(9):869-70
references.pmid: 11528414
references.citation: J Gen Physiol. 2004 Oct;124(4):383-94
references.pmid: 15452199
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1459-64
references.pmid: 9037075
references.citation: J Comput Chem. 2007 Dec;28(16):2618-40
references.pmid: 17894371
references.citation: J Gen Physiol. 2006 Feb;127(2):109-17
references.pmid: 16418400
references.citation: Proteins. 2005 Dec 1;61(4):704-21
references.pmid: 16231289