title: The calmodulin-binding, short linear motif, NSCaTE is conserved in L-type channel ancestors of vertebrate Cav1.2 and Cav1.3 channels.
abstract: NSCaTE is a short linear motif of (xWxxx(I or L)xxxx), composed of residues with a high helix-forming propensity within a mostly disordered N-terminus that is conserved in L-type calcium channels from protostome invertebrates to humans. NSCaTE is an optional, lower affinity and calcium-sensitive binding site for calmodulin (CaM) which competes for CaM binding with a more ancient, C-terminal IQ domain on L-type channels. CaM bound to N- and C- terminal tails serve as dual detectors to changing intracellular Ca(2+) concentrations, promoting calcium-dependent inactivation of L-type calcium channels. NSCaTE is absent in some arthropod species, and is also lacking in vertebrate L-type isoforms, Cav1.1 and Cav1.4 channels. The pervasiveness of a methionine just downstream from NSCaTE suggests that L-type channels could generate alternative N-termini lacking NSCaTE through the choice of translational start sites. Long N-terminus with an NSCaTE motif in L-type calcium channel homolog LCav1 from pond snail Lymnaea stagnalis has a faster calcium-dependent inactivation than a shortened N-termini lacking NSCaTE. NSCaTE effects are present in low concentrations of internal buffer (0.5 mM EGTA), but disappears in high buffer conditions (10 mM EGTA). Snail and mammalian NSCaTE have an alpha-helical propensity upon binding Ca(2+)-CaM and can saturate both CaM N-terminal and C-terminal domains in the absence of a competing IQ motif. NSCaTE evolved in ancestors of the first animals with internal organs for promoting a more rapid, calcium-sensitive inactivation of L-type channels.
authors.affiliation: Department of Chemistry, University of Waterloo, Waterloo, Canada.
authors.forename: Valentina
authors.initials: V
authors.lastname: Taiakina
authors.forename: Adrienne N
authors.initials: AN
authors.lastname: Boone
authors.forename: Julia
authors.initials: J
authors.lastname: Fux
authors.forename: Adriano
authors.initials: A
authors.lastname: Senatore
authors.forename: Danielle
authors.initials: D
authors.lastname: Weber-Adrian
authors.forename: J Guy
authors.initials: JG
authors.lastname: Guillemette
authors.forename: J David
authors.initials: JD
authors.lastname: Spafford
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D005075:Biological Evolution; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D015870:Gene Expression; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D010802:Phylogeny; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017386:Sequence Homology, Amino Acid; D012908:Snails / Q000235:genetics / Q000378:metabolism*
chemical_list: C472073:CACNA1D protein, human; D020746:Calcium Channels, L-Type; D002147:Calmodulin; C419385:L-type calcium channel alpha(1C); D049452:Green Fluorescent Proteins