Structure of Calmodulin Bound to the Hydrophobic IQ Domain of the Cardiac Cav1.2 Calcium Channel

Abstract

Ca2+-dependent inactivation (CDI) and facilitation (CDF) of the Ca(v)1.2 Ca2+ channel require calmodulin binding to a putative IQ motif in the carboxy-terminal tail of the pore-forming subunit. We present the 1.45 A crystal structure of Ca2+-calmodulin bound to a 21 residue peptide corresponding to the IQ domain of Ca(v)1.2. This structure shows that parallel binding of calmodulin to the IQ domain is governed by hydrophobic interactions. Mutations of residues I1672 and Q1673 in the peptide to alanines, which abolish CDI but not CDF in the channel, do not greatly alter the structure. Both lobes of Ca2+-saturated CaM bind to the IQ peptide but isoleucine 1672, thought to form an intramolecular interaction that drives CDI, is buried. These findings suggest that this structure could represent the conformation that calmodulin assumes in CDF.

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

“…Specifically, it contains various phosphorylation residues that allow fast regulatory responses13, as well as the IQ motif, which is a specific interaction domain for calmodulin15. Calmodulin represents the major calcium-dependent modulator of LTCC function, promoting either calcium-dependent inactivation (CDI) or calcium-dependent facilitation (CDF)161718.…”

The Calmodulin Regulator Protein, PEP-19, Sensitizes ATP-induced Ca2+ Release

“…The acidic sequence is deleted in PEP⌬Ac such that Val-26 effectively substitutes for Glu-40 of native PEP-19. We anticipated that a hydrophobic residue at this position would promote association of PEP⌬Ac with both the N-and C-domains of CaM because a Phe residue at the homologous position in the Ca V 1.2 channel anchors its IQ region to the N-domain (22). Residues in the acidic sequence of PEPscram are randomized to determine whether the native sequence is important for modulating Ca 2ϩ binding to CaM or whether a cluster of negative charges is sufficient.…”

“…2 shows that fluorescence from CaM(DA) is not greatly affected by native PEP-19 because it binds preferentially to the C-domain of CaM, but a large decrease in fluorescence is seen upon binding to either PEP⌬Ac or a CaM-binding peptide from CaM kinase II, CKII(293-312), which is known to bind to both domains of CaM (25). As a further test, we generated PEP(E40F), with Phe at the homologous position to the Phe that anchors the IQ motif of the Ca V 1.2 channel to the N-domain of CaM (22). Fig.…”

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

“…2) and is an essential property of calmodulin, which permits this protein to interact with a large and diverse array of interacting partners. The significant conformational changes on binding to its targets (Fallon et al 2005) can increase its affinity for Ca 2þ .…”