Most calmodulin (CaM) targets are α-helices. It is not clear if CaM induces the adoption of an α-helix configuration to its targets or if those targets are selected as they spontaneously adopt an α-helical conformation. Other than an α-helix propensity, there is a great variety of CaM targets with little more in common.One exception to this rule is the IQ site that can be recognized in a number of targets, such as those ion channels belonging to the KCNQ family. Although there is negligible sequence similarity between the IQ motif and the docking site on SK2 channels, both adopt a similar three-dimensional disposition. The isolated SK2 target presents a pre-folded core region that becomes fully α-helical upon binding to CaM. The existence of this pre-folded state suggests the occurrence of capping within CaM targets. In this review, we examine the capping properties within the residues flanking this core domain, and relate known IQ motifs and capping.

Proteinak polimero lineal gisa sintetizatzen dira eta beren jatorrizko egitura tridimentsionalean tolestu behar dira zelulan hainbat funtzio betetzeko. Proteinen tolespena ulertzea funtsezkoa da, tolespen okerrak hainbat gaixotasun neuro-degeneratiboren jatorria direlako. Proteinen tolespena modu koitzultzailean has daiteke, hau da, sortzen ari den peptidoa erribosomari lotuta dagoenean oraindik. Izan ere, zelularen proteinen heren bat baino gehiago erribosomaren tunelaren espazio mugatuan tolesten direla frogatu da, hau da, erribosomaren gainazalarekiko interakzioek modulatuta eta erribosoma-tunelaren beraren mugen pean. Gero eta ebidentzia gehiagok iradokitzen dute erribosomak funtsezko zeregina duela proteinen tolespenean. Erribosomak proteina trinkotzea erraztu dezake, soluzioan ikusten ez diren bitartekoak sortzea eragin dezake edo tolestearen hasiera atzeratu dezake. Hala ere, proteinen koitzulpenezko tolesdura aztertzeak zailtasun handiak ditu, batik bat, egungo teknikek dituzten mugengatik. Hori dela eta, proteinen tolesteari buruzko ikerketa gehienak soluzioan dauden proteinetan oinarritzen dira, proteina tolestuz eta destolestuz egiten direnak, prozesu horretan erribosomak duen rola kontuan hartu gabe. Artikulu honetan, azken urteotan proteinen koitzulpenezko tolestura ikertzeko garatu diren tekniken laburpena egin da.

The family of small-conductance (SK) ion channels is composed of four members (SK1, SK2, SK3, and SK4) involved in neuron-firing regulation. The gating of these channels depends on the intracellular Ca2+ concentration, and their sensitivity to this ion is provided by calmodulin (CaM). This protein binds to a specific region in SK channels known as the calmodulin-binding domain (CaMBD), an event which is essential for their gating. While CaM-binding domains are typically disordered in the absence of CaM, the SK2 channel subtype displays a small pre-folded alpha helical region in its CaMBD even if CaM is not present. This small helix is known to turn into a full alpha-helix upon CaM binding, although the molecular-level details for this conversion are not fully understood yet. In this work, we offer new insights on this physiologically relevant process by means of enhanced sampling, atomistic Hamiltonian replica exchange molecular dynamics simulations, providing a more detailed understanding of CaM binding to this target. Our results show that CaM is necessary for inducing a full alpha-helix along the SK2 CaMBD through hydrophobic interactions with V426 and L427. However, it is also necessary that W431 does not compete for these interactions; the role of the small pre-folded alpha-helix in the SK2 CaMBD would be to stabilize W431 so that this is the case.