Review
Calmodulin as a protein linker and a regulator of adaptor/scaffold proteins

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Highlights

  • Calmodulin can function as a Ca2 +-dependent adaptor protein.

  • Calmodulin can bridge between different domains of the same protein.

  • Calmodulin can link two identical or different target proteins together.

  • These properties are mainly based on the flexibility of the linker region between the two Ca2 + binding lobes.

  • Calmodulin regulates the function of adaptor and scaffold proteins.

Abstract

Calmodulin (CaM) is a universal regulator for a huge number of proteins in all eukaryotic cells. Best known is its function as a calcium-dependent modulator of the activity of enzymes, such as protein kinases and phosphatases, as well as other signaling proteins including membrane receptors, channels and structural proteins. However, less well known is the fact that CaM can also function as a Ca2 +-dependent adaptor protein, either by bridging between different domains of the same protein or by linking two identical or different target proteins together. These activities are possible due to the fact that CaM contains two independently-folded Ca2 + binding lobes that are able to interact differentially and to some degree separately with targets proteins. In addition, CaM can interact with and regulates several proteins that function exclusively as adaptors. This review provides an overview over our present knowledge concerning the structural and functional aspects of the role of CaM as an adaptor protein and as a regulator of known adaptor/scaffold proteins.

Abbreviations

AC
adenylyl cyclase
ALG-2
apoptosis-linked gene 2 product
Alix
ALG-2-interacting protein X
Bcl10
B-cell lymphoma/leukemia protein 10
CaM
calmodulin
CaM-BD
CaM-binding domain
CaM-BP
CaM-binding protein
CARD
caspase-recruitment domain
Carma1
CARD-containing MAGUK protein 1
DR6
death receptor 6
EDTA
ethylenediaminetetraacetic acid
EGFR
epidermal growth factor receptor
EGTA
ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid
Eps15
epidermal growth factor receptor substrate 15
ERα
estrogen receptor α
FADD
Fas-associated protein with death domain
GAD
glutamate decarboxylase
GEF
guanine nucleotide exchange factor
GPCR
G protein-coupled receptor
Grb2/7/10/14
growth factor receptor binding proteins 2/7/10/14
HIV-1
human immunodeficiency virus 1
HRP
horseradish peroxidase
Hsp70/90
heat chock proteins 70/90
IGF
insulin-like growth factor
IQGAP1
Ras GTPase-activating-like protein
JNK
Jun N-terminal kinase
LRP4
low-density lipoprotein receptor-related protein 4
mAKAPβ
muscle A-kinase anchoring protein β
MAP-2
microtubule-associated protein 2
MAPK
mitogen-activated protein kinase
MBP
myelin-binding protein
MINT
Munc-18-interacting protein
MLCK
myosin light-chain kinase
MMDM ID
Molecular Modeling Database Identification Number
Munc13-1
mammalian homolog of Caenorhabditis elegans unc-13p
NDPK
nucleoside diphosphate kinase
NFAT
nuclear factor of activated T cells
NF-κB
nuclear factor κB
NHE1
Na+/H+-exchanger 1
NMDA
N-methyl-d-aspartate
NMR
nuclear magnetic resonance
NRON
non-coding RNA repressor of NFAT
NRIP
nuclear receptor interacting protein
NSCaTE
N-terminal spatial Ca2 + transforming element
NtMKP1
Nicotiana tabacum mitogen-activated protein kinase phosphatase 1
Orai1
Ca2 + release-activated Ca2 + channel protein 1
p75NTR
neurotrophin receptor
PDB ID
Protein Data Bank Identification Number
PI3K
phosphatidylinositol 3-kinase
PH
pleckstrin-homology
PKA
protein kinase A
PKC
protein kinase C
PP2A
protein phosphatase 2A
PTB
phospho-tyrosine binding domain
SH2
Src homology domain 2
SH3
Src homology domain 3
Shc
Src homologous collagen protein
Sos
Son of sevenless
SPB
spindle cell body
SRY
sex-determining region on the Y chromosome
STIM1
stromal interaction molecule 1
TANC
tetratricopeptide repeat-, ankyrin repeat- and coiled-coil region-containing protein
TAT
trans-activator of transcription
TnC
troponin C
TNFR
tumor necrosis factor receptor
TnI
troponin I
TnT
troponin T
TRADD
tumor necrosis factor receptor 1-associated death domain protein
TRPA1
transient receptor potential ankyrin 1
TRPV1
transient receptor potential vanilloid 1
W-7
N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide
W-13
N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide

Keywords

Adaptor proteins
Bridging proteins
Calmodulin
Protein-protein interaction
Scaffold proteins

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