title: Phylogenetic profiles reveal structural/functional determinants of TRPC3 signal-sensing antennae.
abstract: Biochemical assessment of channel structure/function is incredibly challenging. Developing computational tools that provide these data would enable translational research, accelerating mechanistic experimentation for the bench scientist studying ion channels. Starting with the premise that protein sequence encodes information about structure, function and evolution (SF&E), we developed a unified framework for inferring SF&E from sequence information using a knowledge-based approach. The Gestalt Domain Detection Algorithm-Basic Local Alignment Tool (GDDA-BLAST) provides phylogenetic profiles that can model, ab initio, SF&E relationships of biological sequences at the whole protein, single domain and single-amino acid level.1,2 In our recent paper,4 we have applied GDDA-BLAST analysis to study canonical TRP (TRPC) channels1 and empirically validated predicted lipid-binding and trafficking activities contained within the TRPC3 TRP_2 domain of unknown function. Overall, our in silico, in vitro, and in vivo experiments support a model in which TRPC3 has signal-sensing antennae which are adorned with lipid-binding, trafficking and calmodulin regulatory domains. In this Addendum, we correlate our functional domain analysis with the cryo-EM structure of TRPC3.3 In addition, we synthesize recent studies with our new findings to provide a refined model on the mechanism(s) of TRPC3 activation/deactivation.
authors.affiliation: Department of Biology; The Pennsylvania State University; University Park; PA USA.
authors.forename: Kyung Dae
authors.initials: KD
authors.lastname: Ko
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bhardwaj
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Hong
authors.forename: Gue Su
authors.initials: GS
authors.lastname: Chang
authors.forename: Kirill
authors.initials: K
authors.lastname: Kiselyov
authors.forename: Damian B
authors.initials: DB
authors.lastname: van Rossum
authors.forename: Randen L
authors.initials: RL
authors.lastname: Patterson
references.citation: Science. 2006 Oct 6;314(5796):122-5
references.pmid: 17023658
references.citation: Nature. 1999 Jan 21;397(6716):259-63
references.pmid: 9930701
references.citation: J Cell Physiol. 2006 May;207(2):315-21
references.pmid: 16331690
references.citation: Biochem Biophys Res Commun. 2005 Aug 5;333(3):768-77
references.pmid: 15964551
references.citation: Nature. 2005 Mar 3;434(7029):99-104
references.pmid: 15744307
references.citation: Cell. 2003 Sep 19;114(6):777-89
references.pmid: 14505576
references.citation: Mol Cell. 1999 Sep;4(3):423-9
references.pmid: 10518223
references.citation: EMBO J. 2006 Feb 8;25(3):467-78
references.pmid: 16424899
references.citation: Cell Calcium. 2008 May;43(5):506-14
references.pmid: 17942152
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13474-9
references.pmid: 18765810
references.citation: J Biol Chem. 2008 Dec 5;283(49):34384-92
references.pmid: 19043047
references.citation: Nat Chem Biol. 2006 Nov;2(11):596-607
references.pmid: 16998480
references.citation: J Biol Chem. 2003 May 2;278(18):16244-52
references.pmid: 12606542
references.citation: J Mol Biol. 2007 Mar 23;367(2):373-83
references.pmid: 17258231
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2625-30
references.pmid: 14983059
references.citation: Mol Cell. 2007 Feb 23;25(4):491-503
references.pmid: 17317623
references.citation: Neuron. 2006 Nov 9;52(3):485-96
references.pmid: 17088214
references.citation: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):14955-60
references.pmid: 10611319
references.citation: Pflugers Arch. 2005 Oct;451(1):105-15
references.pmid: 15924238
references.citation: Nature. 1998 Dec 3;396(6710):478-82
references.pmid: 9853757
references.citation: Mol Cell. 2004 Aug 27;15(4):635-46
references.pmid: 15327778
references.citation: J Biol Chem. 2008 Nov 21;283(47):32821-30
references.pmid: 18755685
references.citation: J Biol Chem. 2006 Oct 27;281(43):32540-9
references.pmid: 16887806
references.citation: J Biol Chem. 2005 Sep 9;280(36):32035-47
references.pmid: 15994335
references.citation: J Biol Chem. 2003 Aug 1;278(31):29031-40
references.pmid: 12721302
references.citation: Biochim Biophys Acta. 2006 Nov;1761(11):1260-9
references.pmid: 16962825