TCDB is operated by the Saier Lab Bioinformatics Group

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).

References associated with 8.A.82 family:

An, W.F., M.R. Bowlby, M. Betty, J. Cao, H.P. Ling, G. Mendoza, J.W. Hinson, K.I. Mattsson, B.W. Strassle, J.S. Trimmer, and K.J. Rhodes. (2000). Modulation of A-type potassium channels by a family of calcium sensors. Nature 403: 553-556. 10676964
Armacki, M., G. Joodi, S.C. Nimmagadda, L. de Kimpe, G.V. Pusapati, S. Vandoninck, J. Van Lint, A. Illing, and T. Seufferlein. (2014). A novel splice variant of calcium and integrin-binding protein 1 mediates protein kinase D2-stimulated tumour growth by regulating angiogenesis. Oncogene 33: 1167-1180. 23503467
Ben-Johny, M. and D.T. Yue. (2014). Calmodulin regulation (calmodulation) of voltage-gated calcium channels. J Gen Physiol 143: 679-692. 24863929
Blank, B. and J. von Blume. (2017). Cab45-Unraveling key features of a novel secretory cargo sorter at the trans-Golgi network. Eur J. Cell Biol. [Epub: Ahead of Print] 28372832
Brand, I. and K.W. Koch. (2018). Impact of the protein myristoylation on the structure of a model cell membrane in a protein bound state. Bioelectrochemistry 124: 13-21. [Epub: Ahead of Print] 29990597
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] 33667636
Cottle, W.T., C.H. Wallert, K.K. Anderson, M.F. Tran, C.L. Bakker, M.A. Wallert, and J.J. Provost. (2020). Calcineurin homologous protein isoform 2 supports tumor survival via the sodium hydrogen exchanger isoform 1 in non-small cell lung cancer. Tumour Biol 42: 1010428320937863. 32686600
Helassa, N., S.V. Antonyuk, L.Y. Lian, L.P. Haynes, and R.D. Burgoyne. (2017). Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia. Hum Mol Genet 26: 2426-2435. 28398555
Hudlikar, R.R., D. Sargsyan, W. Li, R. Wu, M. Zheng, and A.N. Kong. (2021). Epigenomic, Transcriptomic, and Protective Effect of Carotenoid Fucoxanthin in High Glucose-Induced Oxidative Stress in Mes13 Kidney Mesangial Cells. Chem Res Toxicol. [Epub: Ahead of Print] 33448797
Jerng, H.H. and P.J. Pfaffinger. (2008). Multiple Kv channel-interacting proteins contain an N-terminal transmembrane domain that regulates Kv4 channel trafficking and gating. J. Biol. Chem. 283: 36046-36059. 18957440
Jo, D.G., J. Jang, B.J. Kim, J. Lundkvist, and Y.K. Jung. (2005). Overexpression of calsenilin enhances γ-secretase activity. Neurosci Lett 378: 59-64. 15763173
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. 30763678
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. 34089643
Na, T. and J.B. Peng. (2014). TRPV5: a Ca2+ channel for the fine-tuning of Ca2+ reabsorption. Handb Exp Pharmacol 222: 321-357. 24756712
Núñez, E., A. Muguruza-Montero, and A. Villarroel. (2020). Atomistic Insights of Calmodulin Gating of Complete Ion Channels. Int J Mol Sci 21:. 32075037
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. 26426422
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. 30787866
Rebas, E., T. Boczek, A. Kowalski, K. Kuśmirowska, M. Lisek, and L. Zylińska. (2012). [The role of calmodulin in calcium-dependent signalling in excitable cells]. Postepy Biochem 58: 393-402. 23662433
Riazuddin, S., I.A. Belyantseva, A.P. Giese, K. Lee, A.A. Indzhykulian, S.P. Nandamuri, R. Yousaf, G.P. Sinha, S. Lee, D. Terrell, R.S. Hegde, R.A. Ali, S. Anwar, P.B. Andrade-Elizondo, A. Sirmaci, L.V. Parise, S. Basit, A. Wali, M. Ayub, M. Ansar, W. Ahmad, S.N. Khan, J. Akram, M. Tekin, S. Riazuddin, T. Cook, E.K. Buschbeck, G.I. Frolenkov, S.M. Leal, T.B. Friedman, and Z.M. Ahmed. (2012). Alterations of the CIB2 calcium- and integrin-binding protein cause Usher syndrome type 1J and nonsyndromic deafness DFNB48. Nat. Genet. 44: 1265-1271. 23023331
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. 26173970
Tian, N.X., Y. Xu, J.Y. Yang, L. Li, X.H. Sun, Y. Wang, and Y. Zhang. (2018). KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats. J. Neurosci. 38: 1756-1773. 29335353
Vinberg, F., I.V. Peshenko, J. Chen, A.M. Dizhoor, and V.J. Kefalov. (2018). Guanylate cyclase-activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors. J. Biol. Chem. 293: 7457-7465. 29549122
Wang, H., Y. Yan, Q. Liu, Y. Huang, Y. Shen, L. Chen, Y. Chen, Q. Yang, Q. Hao, K. Wang, and J. Chai. (2007). Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits. Nat Neurosci 10: 32-39. 17187064
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] 32917726
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. 29666364
Zhang, C., X. Wei, G.S. Omenn, and Y. Zhang. (2018). Structure and Protein Interaction-based Gene Ontology Annotations Reveal Likely Functions of Uncharacterized Proteins on Human Chromosome 17. J Proteome Res. [Epub: Ahead of Print] 30265558
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:. 32421152