10.1371/journal.pone.0061765 Valentina Taiakina Valentina Taiakina Adrienne N. Boone Adrienne N. Boone Julia Fux Julia Fux Adriano Senatore Adriano Senatore Danielle Weber-Adrian Danielle Weber-Adrian J. Guy Guillemette J. Guy Guillemette J. David Spafford J. David Spafford The Calmodulin-Binding, Short Linear Motif, NSCaTE Is Conserved in L-Type Channel Ancestors of Vertebrate Cav1.2 and Cav1.3 Channels Public Library of Science 2013 Biochemistry proteins ion channels Evolutionary biology Organismal evolution Animal evolution genomics Genome databases Sequence databases neuroscience Cellular neuroscience proteomics Proteomic databases Sequence analysis linear nscate conserved l-type ancestors vertebrate 2013-04-23 02:29:45 Dataset https://plos.figshare.com/articles/dataset/_The_Calmodulin_Binding_Short_Linear_Motif_NSCaTE_Is_Conserved_in_L_Type_Channel_Ancestors_of_Vertebrate_Cav1_2_and_Cav1_3_Channels_/688985 <div><p>NSCaTE is a short linear motif of (x<u>W</u>xxx(<u>I or L</u>)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<sup>2+</sup> 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, Ca<sub>v</sub>1.1 and Ca<sub>v</sub>1.4 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 LCa<sub>v</sub>1 from pond snail <i>Lymnaea stagnalis</i> 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<sup>2+</sup>-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.</p> </div>