8.A.82 The Calmodulin Calcium Binding Protein (Calmodulin) Family
The calmodulin superfamily is a diverse group of calcium sensors and calcium signal modulators. Most members have 2 active canonical EF hands. Ca2+ binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers. Some such proteins are found elsewhere in TCDB (e.g., under 1.I.1.1.1, Cell division protein 31 (P06704) and under TC# 3.A.5.9.1, Programmed cell death protein 6 (O75340) are calmodulin homologues with 161 and 191 aas, respectively, and the usual two EF hand domains. EF hand domains are found in many protein such as the mitochondrial carrier family members with TC#s 2.A.29.1, 5 and 8, the Kv channel interacting protein 4,KChIP4, with TC# 5.B.1.1.7, the mitochondrial MICU1 protein of 467 aas and 1 TMS with TC# 8.A.44.1.1, and the mitochondrial LETM1 protein with TC# 2.A.97.1.3 (P91927).
Calmodulin regulates the family of voltage-gated CaV1-2 channels which comprises a prominent prototype for ion channel regulation with powerful Ca2+-sensing capabilities. It is mechanistically well defined and rich in biological implications (Ben-Johny and Yue 2014). Calmodulin also regulates TRPV5 which mediates Ca2+ influx into cells (Na and Peng 2014) as well as various other channels, including several voltage-gated calcium channels (VGCCs), transient receptor potential channels (TRPCs), NMDA receptors, calcium channels dependent on cyclic nucleotides and those located in the endoplasmic reticulum such as ryanodine receptors and all isoforms of IP3-dependent receptors (Rebas et al. 2012). Calmodulin binds to the STAS domain of SLC26A5 prestin with a calcium-dependent, one-lobe, binding mode (Costanzi et al. 2021).
New insights regarding four types of tetrameric channels with 6TMS architectures, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1-5, and their regulation by CaM are described structurally (Núñez et al. 2020). Different CaM regions, the N-lobe, C-lobe and EF3/EF4-linker, play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its targets that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies (Núñez et al. 2020).