The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
Functional site class:
Helical calmodulin binding motifs
Functional site description:
Calmodulin (CaM) is a calcium-dependent regulatory protein known to interact with as many as 320 target proteins. It serves as a primary receptor of intracellular Ca²+ capable of responding to wide range of calcium concentration and translates the Ca²+-signal into a cellular process. CaM is composed of two homologous domains, the N- and C-terminal domains (also called N-lobe and C-lobe), capable of independently folding, connected by a flexible linker. Each domain of CaM contains two helix-loop-helix Ca²+-binding motifs. Upon binding of four Ca²+-ions through these motifs, CaM changes its conformation from a closed form to an open one, exposing a hydrophobic surface capable of interacting with different target proteins. The structural plasticity of CaM allows it to bind different targets with different structural features like protein kinases, phosphatases, receptors, ion-channel proteins, phosphodiesterases, and nitric oxide synthases. The Ca²+-dependent CaM binding site often consists of a basic amphipathic
ELMs with same func. site: LIG_CaM_IQ_9  LIG_CaM_NSCaTE_8 
ELM Description:
The IQ motif occurs in myosins and non-myosins proteins and is generally widely distributed in nature. It is sequence with the general consensus [I,L,V]QxxxRGxxx[R,K] with characteristic residues being a hydrophobic residue at position 1, a highly conserved glutamine at position 2, basic charges at positions 6 and 11, and a variable glycine at position 7. Structural studies show that the IQ motif adopts a α-helical conformation, with distinct to no amphipathicity and a net positive charge. The IQ motif enables the Ca2+-independent binding of CaM to target proteins. In some cases (e.g. glycogen phosphorylse b kinase and nitric oxide synthase), the presence of Ca2+ has no effect on CaM-binding, in other cases such as neuromodulin the presence of Ca2+ disables the binding event. The fact that the IQ motif is highly hydrophobic and basic in nature, similar to other Ca2+-CaM binding motifs (LIG_CaM_1-(5-10)-14, LIG_CaM_1-(8)-14 etc.) results in the fact that many IQ motifs can interact with both apo- and Ca2+-CaM. The motif often occurs as multiple tandem repeats in myosins and in some non-myosins proteins. It is sometimes the target of phosphorylation by PKC or PKA proteins. Proteins found to contain at least one IQ domain include myosins, voltage-operated channels, several neuronal growth proteins, phosphatases, sperm surface proteins, Ras exchange proteins, spindle-associated proteins, a RasGAP-like protein and several plant-specific proteins.
Pattern: [ACLIVTM][^P][^P][ILVMFCT]Q[^P][^P][^P][RK][^P]{4,5}[RKQ][^P][^P]
Pattern Probability: 0.0000637
Present in taxons: Acanthamoeba castellanii Argopecten irradians Bos taurus Branchiostoma lanceolatum Caenorhabditis elegans Capra hircus Carassius auratus Cyprinus carpio Dictyostelium discoideum Drosophila melanogaster Eukaryota Gallus gallus Homo sapiens Macaca fascicularis Macropus eugenii Mesocricetus auratus Monodelphis domestica Mus musculus Oryctolagus cuniculus Papio hamadryas Rattus norvegicus Saccharomyces cerevisiae Schizosaccharomyces pombe Serinus canaria Sus scrofa
Interaction Domains:
PDB Structure: 2VAY
o See 75 Instances for LIG_CaM_IQ_9
o Abstract
Calmodulin (CaM) is, as its name implies, a calcium modulated protein. It is a small and ubiquitous protein highly conserved in eukaryotes. CaM binds to its target either in a calcium-dependent or -independent manner. The targets of CaM are numerous and diverse as CaM play an important role in many cellular events in animals and plants. Examples of such events are the involvement in ion transportation, several metabolic pathways, cell proliferation, elongation, cell motility, cytoskeleton organization, stress tolerance and transcription (Berchtold,2014). The Ca2+-saturated form of CaM is conformationally different from its apo-form, which leads to the different target specificity of CaM. The apo-form of CaM binds to the IQ motif of its targets, while the Ca²+-bound form binds to a sequence motif, which consists of hydrophobic residues located at specific positions relative to other amino acids. The binding of calcium to the two helix-loop-helix calcium binding motifs in each of the globular domains of CaM induces a conformational change, that exposes a methionine-rich hydrophobic patch on the surface of each domain of CaM, which it used for targeting its binding partners (Gifford,2011).

There is no specific consensus sequence for CaM binding in Ca2+-dependent manner. The only common feature is that all binding partners have hydrophobic basic peptides that have the propensity to form an alpha helix. Usually the motif consists of 15-30 amino acids. Based on the positions of the key bulky hydrophobic residues, which make important interactions with the CaM, the motifs can be categorized into different groups, such as 1-14, 1-5-8-14, 1-5-10 and 1-8-14. In the classical mode of binding, the Ca2+-loaded CaM clamps a single helical peptide between the lobes. This is only one of the many possible ways in which CaM interacts with its targets. A growing number of non-classical forms of CaM-binding have been identified, where the conformational changes in the CaM domains differ, so it is able to bind targets in unusual forms, like inverted or in an extended conformation. In other cases binding to the target peptide occurs only via the C-terminal lobe and also the stoichiometry of the complex is not always 1:1, forming more than one alpha helix (Tidow,2013). A Novel group of CaM binding motif, NSCaTE has been identified only in Cav1.2 and Cav1.3 Channels.It is an optional, lower affinity and calcium-sensitive binding site for calmodulin (CaM) which competes for CaM binding with the ancient IQ domain on L-type channels (Taiakina,2013). Studies have shown that the differential binding of CaM is due to its structural flexibility, which arise from the flexible linker-movement between the two CaM domains, and also due to the involvement of a large number of methionine residues found in the exposed hydrophobic patches of CaM (Zhang,1998).
Mutations in CaM and also in the CaM-binding regions are associated with many life-threatening conditions. In infants, mutations in CaM affect the calcium signaling events in the heart and lead to cardiac arrhythmias and sudden death of the child (Crotti,2013). Mutations in the CaM-binding region of ryanodine receptors abolish the CaM-binding and induce abnormal hypertrophy with dilatation of the left ventricle, suggesting that CaM-binding is a critical factor for the maintenance of normal function and structure of the left ventricle (Hino,2012). An altered regulation of the CaM-dependent cell cycle and cell proliferation is seen in many tumor cells. Thus targeting CaM or CaM-dependent signalling pathway has been considered a useful strategy for potential therapeutic intervention in cancer.
Due to the flexibility of Calmodulin and its variable binding modes, we have not yet been able to derive reliable motifs for the Ca2+ loaded Calmodulin-binding peptides.
o 17 selected references:

o 9 GO-Terms:

o 75 Instances for LIG_CaM_IQ_9
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O89019 Invs
INVS_MOUSE
556 575 DIAAFKIQAVYKGYKVRKAF TP 2 Mus musculus (House mouse)
O89019 Invs
INVS_MOUSE
915 934 NKAAAVIQRAWRSYQLRKHL TP 3 Mus musculus (House mouse)
P10676 ninaC
NINAC_DROME
1037 1056 VKKVIKVQSMMRALLARKRV TP 3 Drosophila melanogaster (Fruit fly)
2 
P10676 ninaC
NINAC_DROME
1073 1091 DVAASKIQKAFRGFRDRVRL TP 4 Drosophila melanogaster (Fruit fly)
2 
O14830 PPEF2
PPE2_HUMAN
20 38 FKAAALIQRWYRRYVARLEM TP 4 Homo sapiens (Human)
4 
P06836 GAP43
NEUM_BOVIN
32 51 HKAATKIQASFRGHITRKKL TP 3 Bos taurus (Cattle)
2 
Q2WEL1 CBT
Q2WEL1_ORYSA
758 777 IVAALKIQHAFRNYNRKKAM TP 2 Oryza sativa (Rice)
2 
Q54T86 dwwA
DWWA_DICDI
462 480 EEAAVIIQRTFRNHKKQSYN TP 1 Dictyostelium discoideum
Q13698 CACNA1S
CAC1S_HUMAN
1523 1542 FYATFLIQEHFRKFMKRQEE TP 3 Homo sapiens (Human)
2 
P27732 Cacna1d
CAC1D_RAT
1650 1669 FYATFLIQDYFRKFKKRKEQ TP 1 Rattus norvegicus (Norway rat)
P38377 SEC61A1
S61A1_CANFA
13 31 CVILPEIQKPERKIQFKEKV FP 2 Canis lupus familiaris (Dog)
2 
Q5VST9 OBSCN
OBSCN_HUMAN
4876 4892 AAVKIQAAFKGYKVRKEMKQ TP 2 Homo sapiens (Human)
Q9WTU3 Scn8a
SCN8A_MOUSE
1897 1913 SAVVLQRAYRGHLARRGFIC TP 3 Mus musculus (House mouse)
Q5JU85 IQSEC2
IQEC2_HUMAN
351 367 AARTIQTAFRQYRMNKNFER TP 2 Homo sapiens (Human)
O89019 Invs
INVS_MOUSE
559 575 AAFKIQAVYKGYKVRKAFRD TP 3 Mus musculus (House mouse)
O89019 Invs
INVS_MOUSE
918 934 AAAVIQRAWRSYQLRKHLSR TP 3 Mus musculus (House mouse)
Q15051 IQCB1
IQCB1_HUMAN
321 336 SAVIALQRSFRSKRSKMLLE TP 2 Homo sapiens (Human)
Q15051 IQCB1
IQCB1_HUMAN
391 407 SALIIQKHWRGYRERKNFHQ TP 2 Homo sapiens (Human)
P36425 SPA17
SP17_RABIT
114 129 MAALKIQAAFRGHLAREDVK TP 3 Oryctolagus cuniculus (Rabbit)
O14830 PPEF2
PPE2_HUMAN
23 38 KAAALIQRWYRRYVARLEMR TP 3 Homo sapiens (Human)
Q13402 MYO7A
MYO7A_HUMAN
748 763 DRVILLQKVIRGFKDRSNFL TP 3 Homo sapiens (Human)
Q13402 MYO7A
MYO7A_HUMAN
771 787 AATLIQRHWRGHNCRKNYGL TP 3 Homo sapiens (Human)
Q13402 MYO7A
MYO7A_HUMAN
817 833 RIIQFQARCRAYLVRKAFRH TP 3 Homo sapiens (Human)
Q13402 MYO7A
MYO7A_HUMAN
840 856 AVLTVQAYARGMIARRLHQR TP 3 Homo sapiens (Human)
Q99250 SCN2A
SCN2A_HUMAN
1909 1925 SAIIIQRAYRRYLLKQKVKK TP 3 Homo sapiens (Human)
Q9D9K8 Iqcf1
IQCF1_MOUSE
49 65 QVVKIQAWWRGTLVRRSLLH TP 4 Mus musculus (House mouse)
Q9D9K8 Iqcf1
IQCF1_MOUSE
105 121 AVVRLQSWIRMWRIRRRYCR TP 4 Mus musculus (House mouse)
Q9H095 IQCG
DRC9_HUMAN
397 413 SVIKLQAWWRGTMIRREIGG TP 4 Homo sapiens (Human)
Q99104 Myo5a
MYO5A_MOUSE
770 786 ACIRIQKTIRGWLLRKRYLC TP 1 Mus musculus (House mouse)
Q99104 Myo5a
MYO5A_MOUSE
793 808 RAAITVQRYVRGYQARCYAK TP 1 Mus musculus (House mouse)
O65373 BAG5
BAG5_ARATH
54 69 AAAARIQSGYRSYRIRNLYK TP 2 Arabidopsis thaliana (Thale cress)
Q9Y4I1 MYO5A
MYO5A_HUMAN
889 905 AIIYLQCCFRRMMAKRELKK U 1 Homo sapiens (Human)
Q9Y4I1 MYO5A
MYO5A_HUMAN
866 881 HKAVIIQKRVRGWLARTHYK U 1 Homo sapiens (Human)
Q9Y4I1 MYO5A
MYO5A_HUMAN
841 856 AATIVLQSYLRGFLARNRYR U 1 Homo sapiens (Human)
Q9Y4I1 MYO5A
MYO5A_HUMAN
818 834 AATIIQKYWRMYVVRRRYKI U 1 Homo sapiens (Human)
Q9Y4I1 MYO5A
MYO5A_HUMAN
793 808 KAAITMQRYVRGYQARCYAK U 1 Homo sapiens (Human)
Q9Y4I1 MYO5A
MYO5A_HUMAN
770 786 ACIRIQKTIRGWLLRKKYLR U 1 Homo sapiens (Human)
Q92614 MYO18A
MY18A_HUMAN
1192 1208 NLTLFQAACRGYLARQHFKK U 1 Homo sapiens (Human)
Q9UKN7 MYO15A
MYO15_HUMAN
1929 1945 KIILLQSRARGYLARQRYQQ U 1 Homo sapiens (Human)
Q9D552 Spata17
SPT17_MOUSE
111 127 MAVRIQRRWRGFRIRKYCFN U 1 Mus musculus (House mouse)
Q9D552 Spata17
SPT17_MOUSE
75 91 VVTIIQKWWRSYLGRKFYQL U 1 Mus musculus (House mouse)
Q9D552 Spata17
SPT17_MOUSE
52 67 DAAVMIQSWFRGCQVRAYMR U 1 Mus musculus (House mouse)
B6VAM9 spata17
B6VAM9_DANRE
96 112 MAVKIQQRWRGFYVRKYVHN U 1 Danio rerio (Zebrafish)
B6VAM9 spata17
B6VAM9_DANRE
60 75 KNAILIQKTWRGFTARALFR U 1 Danio rerio (Zebrafish)
B6VAM9 spata17
B6VAM9_DANRE
37 52 EAAVRIQSWFRGCQVRAYIR U 1 Danio rerio (Zebrafish)
Q1A5X6 IQCJ
IQCJ_HUMAN
50 65 SKVKIIQRAWREYLQRQEPL U 1 Homo sapiens (Human)
Q39575 ODA2
DYHG_CHLRE
1157 1175 SDNLTRLQVGFKRELIKEVK TP 1 Chlamydomonas reinhardtii
1 
Q39575 ODA2
DYHG_CHLRE
869 887 QCTLNSLQAMKRRLGSKTTT TP 1 Chlamydomonas reinhardtii
1 
P70392 Rasgrf2
RGRF2_MOUSE
206 225 IKKIKKVQSFMRGWLCRRKW TP 2 Mus musculus (House mouse)
P05548 
CAVPT_BRALA
34 52 ISAATRIQASFRMHKNRMAL TP 1 Branchiostoma lanceolatum (Amphioxus)
P40146 Adcy8
ADCY8_RAT
1191 1209 AVVLGLVQSLNRQRQKQLLN TP 3 Rattus norvegicus (Norway rat)
2 
Q6W8Q3 Pcp4l1
PC4L1_MOUSE
46 65 EKAALAIQGKFRRFQKRKKD TP 1 Mus musculus (House mouse)
P48539 PCP4
PCP4_HUMAN
40 59 ERAAVAIQSQFRKFQKKKAG TP 2 Homo sapiens (Human)
P19524 MYO2
MYO2_YEAST
833 851 VNCATLLQAAYRGHSIRANV TP 2 Saccharomyces cerevisiae S288c
P19524 MYO2
MYO2_YEAST
808 827 SQAIKYLQNNIKGFIIRQRV TP 2 Saccharomyces cerevisiae S288c
Q9HD67 MYO10
MYO10_HUMAN
789 808 KKAAIVFQKQLRGQIARRVY TP 2 Homo sapiens (Human)
2 
Q9HD67 MYO10
MYO10_HUMAN
766 785 LYCVVIIQKNYRAFLLRRRF TP 2 Homo sapiens (Human)
2 
Q03479 myoE
MYOE_DICDI
719 738 RKAAIKIQLFYRSYRYKKWF TP 4 Dictyostelium discoideum
3 
Q03479 myoE
MYOE_DICDI
697 715 PRIVTLIQKTWRGYRARSKW TP 4 Dictyostelium discoideum
3 
P22467 myoA
MYOA_DICDI
746 765 TLAAIKIQRTYRGWLLVREC TP 4 Dictyostelium discoideum
3 
Q14524 SCN5A
SCN5A_HUMAN
1902 1921 EVSAMVIQRAFRRHLLQRSL TP 5 Homo sapiens (Human)
2 
P15390 Scn4a
SCN4A_RAT
1721 1740 EVCAIKIQRAYRRHLLQRSV TP 4 Rattus norvegicus (Norway rat)
2 
Q9WTU3 Scn8a
SCN8A_MOUSE
1894 1913 EVSAVVLQRAYRGHLARRGF TP 3 Mus musculus (House mouse)
2 
Q9WTI7 Myo1c
MYO1C_MOUSE
758 777 KRSAICIQSWWRGTLGRRKA TP 2 Mus musculus (House mouse)
2 
Q9WTI7 Myo1c
MYO1C_MOUSE
735 754 QSLATKIQAAWRGFHWRQKF TP 2 Mus musculus (House mouse)
2 
P04774 Scn1a
SCN1A_RAT
1916 1935 EVSAVIIQRAYRRHLLKRTV TP 4 Rattus norvegicus (Norway rat)
2 
P35722 NRGN
NEUG_BOVIN
27 46 NAAAAKIQASFRGHMARKKI TP 1 Bos taurus (Cattle)
P40421 rdgC
RDGC_DROME
6 25 IRAAIFIQKWYRRHQARREM TP 3 Drosophila melanogaster (Fruit fly)
2 
P46940 IQGAP1
IQGA1_HUMAN
836 854 INDIIKIQAFIRANKARDDY TP 1 Homo sapiens (Human)
P46940 IQGAP1
IQGA1_HUMAN
806 825 KDEVVKIQSLARMHQARKRY TP 1 Homo sapiens (Human)
Q13936 CACNA1C
CAC1C_HUMAN
1666 1685 FYATFLIQEYFRKFKKRKEQ TP 2 Homo sapiens (Human)
2 
P15381 CACNA1C
CAC1C_RABIT
1648 1667 FYATFLIQEYFRKFKKRKEQ TP 1 Oryctolagus cuniculus (Rabbit)
Q63357 Myo1d
MYO1D_RAT
699 717 VRVVLFLQKVWRGTLARMRY TP 1 Rattus norvegicus (Norway rat)
P04775 Scn2a
SCN2A_RAT
1906 1925 EVSAIVIQRAYRRYLLKQKV TP 2 Rattus norvegicus (Norway rat)
2 
P53141 MLC1
MLC1_YEAST
84 102 EDFVKAFQVFDKESTGKVSV TP 0 Saccharomyces cerevisiae (Baker"s yeast)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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