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).

This family belongs to the Calmodulin/Calcineurin/KChIP (CaCa) Superfamily.



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Ben-Johny, M. and D.T. Yue. (2014). Calmodulin regulation (calmodulation) of voltage-gated calcium channels. J Gen Physiol 143: 679-692.

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Costanzi, E., A. Coletti, B. Zambelli, A. Macchiarulo, M. Bellanda, and R. Battistutta. (2021). Calmodulin binds to the STAS domain of SLC26A5 prestin with a calcium-dependent, one-lobe, binding mode. J Struct Biol 213: 107714. [Epub: Ahead of Print]

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Jung, D.W., P.C. Bradshaw, M. Litsky, and D.R. Pfeiffer. (2004). Ca2+ transport in mitochondria from yeast expressing recombinant aequorin. Anal Biochem 324: 258-268.

Key, J., A.K. Mueller, S. Gispert, L. Matschke, I. Wittig, O. Corti, C. Münch, N. Decher, and G. Auburger. (2019). Ubiquitylome profiling of Parkin-null brain reveals dysregulation of calcium homeostasis factors ATP1A2, Hippocalcin and GNA11, reflected by altered firing of noradrenergic neurons. Neurobiol Dis 127: 114-130.

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Lee, A., R.E. Westenbroek, F. Haeseleer, K. Palczewski, T. Scheuer, and W.A. Catterall. (2002). Differential modulation of Ca(v)2.1 channels by calmodulin and Ca2+-binding protein 1. Nat Neurosci 5: 210-217.

Liang, X., X. Qiu, G. Dionne, C.L. Cunningham, M.L. Pucak, G. Peng, Y.H. Kim, A. Lauer, L. Shapiro, and U. Müller. (2021). CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells. Neuron. 109: 2131-2149.e15.

Na, T. and J.B. Peng. (2014). TRPV5: a Ca2+ channel for the fine-tuning of Ca2+ reabsorption. Handb Exp Pharmacol 222: 321-357.

Núñez, E., A. Muguruza-Montero, and A. Villarroel. (2020). Atomistic Insights of Calmodulin Gating of Complete Ion Channels. Int J Mol Sci 21:.

Patel, K., A.P. Giese, J.M. Grossheim, R.S. Hegde, R.S. Hegde, M. Delio, J. Samanich, S. Riazuddin, G.I. Frolenkov, J. Cai, Z.M. Ahmed, and B.E. Morrow. (2015). A Novel C-Terminal CIB2 (Calcium and Integrin Binding Protein 2) Mutation Associated with Non-Syndromic Hearing Loss in a Hispanic Family. PLoS One 10: e0133082.

Peraza, D.A., P. Cercós, P. Miaja, Y.G. Merinero, L. Lagartera, P.G. Socuéllamos, C. Izquierdo García, S.A. Sánchez, A. López-Hurtado, M. Martín-Martínez, L.A. Olivos-Oré, J.R. Naranjo, A.R. Artalejo, M. Gutiérrez-Rodríguez, and C. Valenzuela. (2019). Identification of IQM-266, a Novel DREAM Ligand That Modulates K4 Currents. Front Mol Neurosci 12: 11.

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Seco, C.Z., A.P. Giese, S. Shafique, M. Schraders, A.M. Oonk, M. Grossheim, J. Oostrik, T. Strom, R. Hegde, E. van Wijk, G.I. Frolenkov, M. Azam, H.G. Yntema, R.H. Free, S. Riazuddin, J.B. Verheij, R.J. Admiraal, R. Qamar, Z.M. Ahmed, and H. Kremer. (2016). Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells. Eur J Hum Genet 24: 542-549.

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Wu, C.J., X. Li, C.L. Sommers, K. Kurima, S. Huh, G. Bugos, L. Dong, W. Li, A.J. Griffith, and L.E. Samelson. (2020). Expression of a TMC6-TMC8-CIB1 heterotrimeric complex in lymphocytes is regulated by each of the components. J. Biol. Chem. [Epub: Ahead of Print]

Yang, Y., N. Liu, Y. He, Y. Liu, L. Ge, L. Zou, S. Song, W. Xiong, and X. Liu. (2018). Improved calcium sensor GCaMP-X overcomes the calcium channel perturbations induced by the calmodulin in GCaMP. Nat Commun 9: 1504.

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Zhu, L., R. Sardana, D.K. Jin, and S.D. Emr. (2020). Calcineurin-dependent regulation of endocytosis by a plasma membrane ubiquitin ligase adaptor, Rcr1. J. Cell Biol. 219:.


TC#NameOrganismal TypeExample

Calmodulin regulates various 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).  It also mediates secretion in animals of small intron-less proteins (Shao and Hegde, 2011).


Calmodulin of Homo sapiens (P62158)


Calcium and integrin-binding family member 2, CIB2 or KIP2, of 187 aas.  It is a calcium-binding protein critical for proper photoreceptor cell maintenance and function. It plays a role in intracellular calcium homeostasis by decreasing ATP-induced calcium release (Riazuddin et al. 2012, Seco et al. 2016, Patel et al. 2015). It is essential for mechanotransduction. CIB3 (TC# 8.A.82.1.11) is functionally and structurally equivalent to CIB2 (Liang et al. 2021). CIB2 and CIB3 are structurally similar to KChIP proteins, auxiliary subunits of voltage-gated Kv4 channels. CIB2 and CIB3 bind to TMC1/2 through a domain in TMC1/2 flanked by TMSs 2 and 3. The co-crystal structure of the CIB-binding domain in TMC1 with CIB3 revealed that interactions are mediated through a conserved CIB hydrophobic groove, similar to KChIP1 binding of Kv4. Functional studies in mice showed that CIB2 regulates TMC1/2 localization and function in hair cells, processes that are affected by deafness-causing CIB2 mutations. Thus, CIB2 and CIB3 are MET channel auxiliary subunits with striking similarity to Kv4 channel auxiliary subunits (Liang et al. 2021). CIB3 or KIP3 is 61% identical to CIB2 and is the same length.


CIB2 of Homo sapiens


Calcium binding protein 1, CABP1, of 370 aas and 0 TMSs. It modulates the calcium-dependent activity of inositol 1,4,5-triphosphate receptors (ITPRs) (Haynes et al. 2004) and inhibits agonist-induced intracellular calcium signaling (Zhou et al. 2005). It also enhances inactivation and does not support calcium-dependent facilitation of voltage-dependent P/Q-type calcium channels (Lee et al. 2002). It causes calcium-dependent facilitation and inhibits inactivation of L-type calcium channels by binding to the same sites as calmodulin in the C-terminal domain of CACNA1C, but  it has an opposite effect on channel function (Zhou et al. 2004). It suppresses the calcium-dependent inactivation of CACNA1D and inhibits TRPC5 channels (Kinoshita-Kawada et al. 2005) while preventing NMDA receptor-induced cellular degeneration.


CABP1 of Homo sapiens


Calretinin (Calbindin) of 271 aas and no TMS.  Plays a role in the regulation of cytoplasmic calcium concentrations.  It is a calcium-binding protein abundant in auditory neurons.

Calretinin of Homo sapiens


Calmodulin-like protein, CML6, of 154 aas. May regulate calcium-dependent activities in the endoplasmic reticulum lumen or post-ER compartment. Isoform 5 may be involved in the exocytosis of zymogens by pancreatic acini.

CML6 of Arabidopsis thaliana (Mouse-ear cress)


Calmodulin-like protein, CaM, of 151 aas,

CaM of Drosophila melanogaster (Fruit fly)


Uncharacterized protein of 148 aas

UP of Cladophialophora yegresii


Calcineurin B-like protein of 195 aas, CHP1 or CHP. Calcineurin B homologous proteins 1 and 2 activate NHE1 (TC#2.A.36.1.13) (Cottle et al. 2020). It also regulates endocytosis by a plasma membrane ubiquitin ligase adaptor, Rcr1 (Zhu et al. 2020).

CHP1 of Homo sapiens


RCaMP of 432 aas and 0 TMSs. GCaMP, containing a C-terminal CaM (calmodulin) domain, interferes with both gating and signaling of L-type calcium channels (CaV1). GCaMP acts as an impaired apoCaM and Ca2+/CaM, both critical to CaV1 (Yang et al. 2018).

RCaMP of Entacmaea quadricolor (Bubble-tip anemone) (Parasicyonis actinostoloides)


Calmodulin-like protein 4 of 205 aas and possibly 2 or 3 N-terminal TMSs.

Calmodulin-like protein 4 of Sinocyclocheilus anshuiensis


Calcium and integrin-binding protein 1, CIB1, CIB, KIP, PAKDCIP, of 191 aas. It is a calcium-binding protein that plays a role in the regulation of numerous cellular processes, such as cell differentiation, cell division, cell proliferation, cell migration, thrombosis, angiogenesis, cardiac hypertrophy and apoptosis (Armacki et al. 2014).  It forms a heterotrimeric complex with TMC6 (TC# 1.A.17.4.10) and TMC8 (TC# 1.A.17.4.11), stabilizing the complex (Wu et al. 2020).

CIB1 of Homo sapiens


TC#NameOrganismal TypeExample
8.A.82.2.1Calcineurin B-like protein 8PlantsArabidopsis thaliana

Kv channel-interacting protein 4 (KChIP4) (A-type potassium channel modulatory protein 4) (Calsenilin-like protein) (Potassium channel-interacting protein 4).  These proteins have N-terminal variants due to the presence of multiple start sites (Jerng and Pfaffinger 2014). Novel long interspersed element-1 (L1) retrotransposon insertions in several genes associated with seizures/epilepsy, including a de novo somatic L1 retrotransposition in KCNIP4, have been identified (Doyle et al. 2021).


KCNIP4 of Homo sapiens


Salt overly sensitive-3, SOS3 of 222 aas.  The salt stress-induced SALT-OVERLY-SENSITIVE (SOS) pathway in Arabidopsis thaliana involves the perception of a calcium signal by the SOS3 and SOS3-like CALCIUM-BINDING PROTEIN8 (SCaBP8) calcium sensors, which then interact with and activate the SOS2 protein kinase (9.B.106.3.4), forming a complex at the plasma membrane that activates the SOS1 Na⁺/H⁺ exchanger (2.A.36.7.6) (Lin et al. 2014).


SOS3 of Arabidopsis thaliana


The K+-voltage-gated ion channel interacting protein, KCNIP2 or KCHIP2 protein of 270 aas, a regulator and subunit of K+ channels such as Kv4.3 and Kv1.4 as well as cardiac L-type Ca+ channels (Thomsen et al. 2009; Hovind et al. 2011; Wang et al. 2013).  It plays a role in the regulation of ion channel function and stress responses (Hudlikar et al. 2021).


KCHIP2 of Homo sapiens


Calsenilin (KCHIP3, KCNIP3, CSEN, DREAM) of 256 aas and 0 TMSs.  Regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels, such as KCND2/Kv4.2 and KCND3/Kv4.3. Modulates channel expression at the cell membrane, gating characteristics, inactivation kinetics and rate of recovery from inactivation in a calcium-dependent and isoform-specific manner (Jerng and Pfaffinger 2008). Interacts with TRPV1 (TC# 1.A.4.2.1) and alleviates inflammatory hyperalgesia (Tian et al. 2018). IQM-266 is a chemical that may allow a better understanding of DREAM physiological role as well as modulation of neuronal I A in pathological processes (Peraza et al. 2019). Overexpression of calsenilin enhances gamma-secretase activity (TC# 4.G.1) (Jo et al. 2005).


Calsenilin of Homo sapiens


Kv channel-interacting protein, KChIP-1 or KCNIP1 of 227 aas and 0 TMSs.  It is a regulatory subunit of Kv4/D (Shal)-type voltage-gated rapidly inactivating A-type potassium channels. It regulates channel density and influences inactivation kinetics and the rate of recovery from inactivation in a calcium-dependent and isoform-specific manner. In vitro, it modulates KCND1/Kv4.1 and KCND2/Kv4.2 currents and increases the presence of KCND2 at the cell surface (Wang et al. 2007; An et al. 2000).

KChIP-1 of Homo sapiens


Recoverin, of 200 aas, has been mplicated in the pathway from retinal rod guanylate cyclase to rhodopsin. It may be involved in the inhibition of the phosphorylation of rhodopsin in a calcium-dependent manner as the calcium-bound recoverin prolongs the photoresponse. It is a myristoylated protein, and myristoylation causes membrane association (Brand and Koch 2018).

Recoverin of Homo sapiens


Hippocalcin, a Ca2+-binding protein of 193 aas. It may play a role in the regulation of voltage-dependent calcium channels (Helassa et al. 2017). It may also play a role in cyclic-nucleotide-mediated signaling through the regulation of adenylate and guanylate cyclases.  Parkin-null brains show dysregulation of this calcium homeostasis factor as well as ATP1A2 and GNA11, reflected by altered firing of noradrenergic neurons (Key et al. 2019).


Hippocalcin of Homo sapiens


Guanylyl cyclase-activating protein 2 of 200 aas, GucA1B or Gcap2. It stimulates two retinal guanylyl cyclases (GCs) GUCY2D and GUCY2F when the free calcium ion concentration is low, and inhibits them when the free calcium ion concentration is elevated. This Ca2+-sensitive regulation of GCs is a key event in the recovery of the dark state of rod photoreceptors following light exposure. It may be involved in the cone photoreceptor response and recovery in bright light. Light activates a G protein signaling cascade, which closes cGMP-gated channels and decreases Ca2+ levels in photoreceptor outer segment because of continuing Ca2+ extrusion by NCKXs (Vinberg et al. 2018).


GucA1B of Homo sapiens


TC#NameOrganismal TypeExample

45 kDa Ca2+-binding protein of 362 aas with an N-terminal TMS, SDF4 or CAB45. Cab45 mediates sorting of a subset of secretory proteins at the trans-Golgi network. In response to Ca2+ influx, Cab45 forms oligomers, enabling it to bind a variety of specific cargo molecules (Blank and von Blume 2017). It has an internal repeat involving residues 47 - 163 and residues 210 - 347.


CAB45 of Homo sapiens


Reticulocalbin-2 (calumenin-like protein) of 405 aas and 1 N-terminal TMS. These proteins are characterized by at least one EF-hand calcium binding motif, and they belong to a diverse superfamily of calcium sensors and calcium signal modulators. Most members have 2 active canonical EF hands.

Reticulocalbin-2 of Vigna radiata


TC#NameOrganismal TypeExample

EF-hand calcium-binding domain-containing protein 3, EFCAB3, of 438 aas and 0 TMSs (Zhang et al. 2018).

EFCAB3 of Homo sapiens


TC#NameOrganismal TypeExample

Aequorin-1 of 196 aas and 0 TMSs. It is a Ca2+-dependent bioluminescence photoprotein that displays an emission peak at 470 nm (blue light). Trace amounts of calcium ion trigger the intramolecular oxidation of the chromophore, coelenterazine, into coelenteramide and CO2 with the concomitant emission of light (). Characteristics of the aequorin-expressing yeast strains appear suitable for its use in expression-based methods directed at cloning Ca2+ transporters from mammalian mitochondria and for further examining the interrelationships between mitochondrial and cytoplasmic Ca2+ in yeast (Jung et al. 2004).


Aequorin-1 of Aequorea victoria (Water jellyfish) (Mesonema victoria)