Proteins with calmodulin-like domains: structures and functional roles

  • Antonio VillaloboEmail author
  • María González-Muñoz
  • Martin W. BerchtoldEmail author


The appearance of modular proteins is a widespread phenomenon during the evolution of proteins. The combinatorial arrangement of different functional and/or structural domains within a single polypeptide chain yields a wide variety of activities and regulatory properties to the modular proteins. In this review, we will discuss proteins, that in addition to their catalytic, transport, structure, localization or adaptor functions, also have segments resembling the helix-loop-helix EF-hand motifs found in Ca2+-binding proteins, such as calmodulin (CaM). These segments are denoted CaM-like domains (CaM-LDs) and play a regulatory role, making these CaM-like proteins sensitive to Ca2+ transients within the cell, and hence are able to transduce the Ca2+ signal leading to specific cellular responses. Importantly, this arrangement allows to this group of proteins direct regulation independent of other Ca2+-sensitive sensor/transducer proteins, such as CaM. In addition, this review also covers CaM-binding proteins, in which their CaM-binding site (CBS), in the absence of CaM, is proposed to interact with other segments of the same protein denoted CaM-like binding site (CLBS). CLBS are important regulatory motifs, acting either by keeping these CaM-binding proteins inactive in the absence of CaM, enhancing the stability of protein complexes and/or facilitating their dimerization via CBS/CLBS interaction. The existence of proteins containing CaM-LDs or CLBSs substantially adds to the enormous versatility and complexity of Ca2+/CaM signaling.


α-Actinin Calcineurin Calpain Epidermal growth factor receptor Glycerol-3-phosphate dehydrogenase NADPH oxidases Na+/H+ exchanger Plasma membrane Ca2+-ATPase Protein kinases 



Actin-depolymerizing factor




Calcium and internalization




CaM-binding domain


CaM-dependent protein kinase-II


CaM-like domain


Calcineurin A


Calcineurin B


Calmodulin binding site


Cyclin-dependent kinase


CaM-like domain protein kinase/Ca2+-dependent protein kinase


Cellular erythroblastic leukemia viral oncogene homologue


Calmodulin-like binding site


Cartilage oligomeric matrix protein


Death-associated protein kinase 1


Endoplasmic reticulum


Erythroblastic leukemia viral oncogene homologues 1/2/3/4


Epidermal growth factor


EGF receptor


EGFR cytosolic region


Fluorescence resonance energy transfer


Follicle-stimulating hormone


Glycerol-3-phosphate dehydrogenase


Immunoglobulins A/G




Mitogen-activated protein kinase 1


Myosin light-chain kinase


Na+/H+ exchanger 1


Nuclear localization sequence


Nuclear magnetic resonance


NADPH oxidase 5


Reactive oxygen species


Lotus intrinsic membrane protein 2


Phosphatidylinositol 4,5-bisphosphate


cGMP-dependent protein kinase


Phospholipase Cγ


Plasma membrane Ca2+-ATPase


Serine-repeat antigen 5


Transient receptor potential



Original work in the authors laboratories were funded by the Secretaría de Estado de Investigación, Desarrollo e Innovación Grant SAF2014-52048-R, and the Consejería de Educación, Juventud y DeportesComunidad de Madrid Grant B2017/BMD-36 involving contributions from the European Funds for Regional Development (EFRD) and the Social European Fund (SEF) (to AV); the Danish Research Council Grant DFF-4004-00560, the AP Møller Foundation, Dagmar Marshalls Foundation, Einar Willumsen Foundation, Aase and Ejnar Danielsen Foundation, Wedell Wedellsborg Foundation, Frænkels Foundation and the Danish Heart Foundation Grant 13-04-R94-A4547-2280 (to MWB).


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Cancer BiologyInstituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de MadridMadridSpain
  2. 2.Instituto de Investigaciones Sanitarias, Hospital Universitario La Paz, Edificio IdiPAZMadridSpain
  3. 3.Department of BiologyUniversity of CopenhagenCopenhagenDenmark

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