IQ

Short calmodulin-binding motif containing conserved Ile and Gln residues.

• SMART accession number: SM00015
• Description: Calmodulin-binding motif.
• Interpro abstract (IPR000048):

  The IQ motif is an extremely basic unit of about 23 amino acids, whose conserved core usually fits the consensus A-x(3)-I-Q-x(2)-F-R-x(4)-K-K. The IQ motif, which can be present in one or more copies, serves as a binding site for different EF-hand proteins including the essential and regulatory myosin light chains, calmodulin (CaM), and CaM-like proteins [ (PUBMED:1558751) (PUBMED:9141499) ].Many IQ motifs are protein kinase C (PKC) phosphorylation sites [ (PUBMED:1824695) (PUBMED:8424932) ].

  Resolution of the 3D structure of scallop myosin has shown that the IQ motif forms a basic amphipathic helix [ (PUBMED:8127365) ].

  Some proteins known to contain an IQ motif are listed below:

  • A number of conventional and unconventional myosins.
  • Neuromodulin (GAP-43). This protein is associated with nerve growth. It is a major component of the motile "growth cones" that form the tips of elongating axons.
  • Neurogranin (NG/p17). Acts as a "third messenger" substrate of protein kinase C-mediated molecular cascades during synaptic development and remodeling.
  • Sperm surface protein Sp17.
  • Ras GTPase-activating-like protein IQGAP1. IQGAP1 contains 4 IQ motifs.

  This entry covers the entire IQ motif.

• GO function: protein binding (GO:0005515)

There are 165951 IQ domains in 60575 proteins in SMART's nrdb database.

Cellular role (predicted cellular role)

Binding / catalysis: Ca2+-binding

Literature (relevant references for this domain)

Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

• Deloulme JC, Prichard L, Delattre O, Storm DR
• The prooncoprotein EWS binds calmodulin and is phosphorylated by protein kinase C through an IQ domain.
• J Biol Chem. 1997; 272: 27369-77

A growing family of proteins is regulated by protein kinase C and calmodulin through IQ domains, a regulatory motif originally identified in neuromodulin (Alexander, K. A., Wakim, B. T., Doyle, G. S., Walsh, K. A., and Storm, D. R. (1988) J. Biol. Chem. 263, 7544-7549). Here we report that EWS, a nuclear RNA-binding prooncoprotein, contains an IQ domain, is phosphorylated by protein kinase C, and interacts with calmodulin. Interestingly, PKC phosphorylation of EWS inhibits its binding to RNA homopolymers, and conversely, RNA binding to EWS interferes with PKC phosphorylation. Several other RNA-binding proteins, including TLS/FUS and PSF, co-purify with EWS. PKC phosphorylation of these proteins also inhibits their binding to RNA in vitro. These data suggest that PKC may regulate interactions of EWS and other RNA-binding proteins with their RNA targets and that IQ domains may provide a regulatory link between Ca2+ signal transduction pathways and RNA processing.

• Rhoads AR, Friedberg F
• Sequence motifs for calmodulin recognition.
• FASEB J. 1997; 11: 331-40

Calmodulin (CaM) is recognized as a major calcium sensor and orchestrator of regulatory events through its interaction with a diverse group of cellular proteins. Many investigations have focused on defining the region of interaction between CaM and its cellular targets and the action of CaM on target protein function. Because CaM can bind with high affinity to a relatively small alpha-helical region of many proteins, success in clearly defining the essential elements of CaM binding motifs seems feasible and should provide a means of identifying CaM binding proteins. Three recognition motifs for CaM interaction are discussed in the context of experimental investigations of a variety of CaM target proteins. A modified version of the IQ motif as a consensus for Ca2+-independent binding and two related motifs for Ca2+-dependent binding, termed 18-14 and 1-5-10 based on the position of conserved hydrophobic residues, are proposed. Although considerable sequence diversity is observed among the different binding regions, these three classes of recognition motifs exist for many of the known CaM binding proteins.

• Houdusse A, Silver M, Cohen C
• A model of Ca(2+)-free calmodulin binding to unconventional myosins reveals how calmodulin acts as a regulatory switch.
• Structure. 1996; 4: 1475-90

BACKGROUND: In contrast to conventional muscle myosins, where two different light chains (LCs) stabilize the elongated regulatory domain (RD) region of the head portion of the molecule, unconventional myosins are a diverse group of motors in which from one to six calmodulin (CaM) subunits are bound tandemly to the RD. In both cases, the heavy chains of the RDs have special sequences called "IQ motifs' to which the LCs or CaM bind. A previously puzzling aspect of certain unconventional myosins is their unusual mode of regulation, where activation of motility occurs at low levels of Ca2+. Although the atomic structure of the conventional muscle myosin RD has been determined, no crystallographic structure of the RD of an unconventional myosin is yet available. RESULTS: We have constructed a model of vertebrate CaM bound to the first IQ motif present in the neck region of an unconventional myosin (chicken brush border myosin I), using strict binding rules derived from the crystal structure of the scallop RD. The model accounts for aspects of the regulation of many unconventional myosins where CaM is bound at low levels of Ca2+ and released or changed in conformation at high levels of Ca2+. The conformational changes as a function of Ca2+ depend not only on the precise sequence of the IQ motifs but also on the interactions between CaM molecules bound to adjacent sites on the myosin heavy chain. CONCLUSIONS: According to our model, the full versatility of CaM binding to target peptides is displayed in the regulation of unconventional myosins. At low concentrations of Ca2+, CaM binds in a manner similar to the LCs of conventional myosins. At higher Ca2+ concentrations, CaM changes conformation and acts as a switch to regulate the activity of the unconventional myosin molecules.

• Xie X et al.
• Structure of the regulatory domain of scallop myosin at 2.8 A resolution.
• Nature. 1994; 368: 306-12

The regulatory domain of scallop myosin is a three-chain protein complex that switches on this motor in response to Ca2+ binding. This domain has been crystallized and the structure solved to 2.8 A resolution. Side-chain interactions link the two light chains in tandem to adjacent segments of the heavy chain bearing the IQ-sequence motif. The Ca(2+)-binding site is a novel EF-hand motif on the essential light chain and is stabilized by linkages involving the heavy chain and both light chains, accounting for the requirement of all three chains for Ca2+ binding and regulation in the intact myosin molecule.

• Mercer JA, Seperack PK, Strobel MC, Copeland NG, Jenkins NA
• Novel myosin heavy chain encoded by murine dilute coat colour locus.
• Nature. 1991; 349: 709-13

Hundreds of murine dilute mutations have been identified and analysed, making dilute one of the best genetically characterized of all mammalian loci. The recessive dilute (d) coat colour mutation carried by many inbred strains of mice produces a lightening of coat colour, caused by an abnormal adendritic melanocyte morphology that results in an uneven release of pigment granules into the developing hair shaft. Most dilute alleles (dilute-lethal) also produce a neurological defect, characterized by convulsions and opisthotonus, apparent at 8-10 days of age and continuing until the death of the animal at 2-3 weeks of age. The discovery that the original dilute allele (now termed dilute-viral or dV) is the result of the integration of an ecotropic murine leukaemia provirus has allowed the cloning of genomic DNA and in this study complementary DNA, from the dilute locus. The predicted dilute amino-acid sequence indicates that dilute encodes a novel type of myosin heavy chain, with a tail, or C-terminal, region that has elements of both type II (alpha-helical coiled-coil) and type I (non-coiled-coil) myosin heavy chains. Dilute transcripts are differentially expressed in both embryonic and adult tissues and are very abundant in neurons of the central nervous system, cephalic ganglia, and spinal ganglia. These results suggest an important role for the dilute gene product in the elaboration, maintenance, or function of cellular processes of melanocytes and neurons.

Disease (disease genes where sequence variants are found in this domain)

SwissProt sequences and OMIM curated human diseases associated with missense mutations within the IQ domain.

Protein	Disease
Unconventional myosin-VIIa (Q13402) (SMART)	OMIM:276903: Usher syndrome, type 1B ; Deafness, autosomal recessive 2, neurosensory OMIM:600060: Deafness, autosomal dominant 11, neurosensory OMIM:601317:
UNKNOWN (SMART)	OMIM:160760: Cardiomyopathy, familial hypertrophic, 1 OMIM:192600: ?Central core disease, one form

Metabolism (metabolic pathways involving proteins which contain this domain)

% proteins involved	KEGG pathway ID	Description
71.22	map04530	Tight junction
14.39	map04810	Regulation of actin cytoskeleton
5.76	map04010	MAPK signaling pathway
4.32	map00230	Purine metabolism
2.88	map00380	Tryptophan metabolism
1.44	map00785	Lipoic acid metabolism

This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with IQ domain which could be assigned to a KEGG orthologous group, and not all proteins containing IQ domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

Structure (3D structures containing this domain)

3D Structures of IQ domains in PDB

PDB code	Title
1b7t	MYOSIN DIGESTED BY PAPAIN
1br1	SMOOTH MUSCLE MYOSIN MOTOR DOMAIN-ESSENTIAL LIGHT CHAIN COMPLEX WITH MGADP.ALF4 BOUND AT THE ACTIVE SITE
1br4	SMOOTH MUSCLE MYOSIN MOTOR DOMAIN-ESSENTIAL LIGHT CHAIN COMPLEX WITH MGADP.BEF3 BOUND AT THE ACTIVE SITE
1dfk	NUCLEOTIDE-FREE SCALLOP MYOSIN S1-NEAR RIGOR STATE
1dfl	SCALLOP MYOSIN S1 COMPLEXED WITH MGADP:VANADATE-TRANSITION STATE
1i84	CRYO-EM STRUCTURE OF THE HEAVY MEROMYOSIN SUBFRAGMENT OF CHICKEN GIZZARD SMOOTH MUSCLE MYOSIN WITH REGULATORY LIGHT CHAIN IN THE DEPHOSPHORYLATED STATE. ONLY C ALPHAS PROVIDED FOR REGULATORY LIGHT CHAIN. ONLY BACKBONE ATOMS PROVIDED FOR S2 FRAGMENT.
1kk7	SCALLOP MYOSIN IN THE NEAR RIGOR CONFORMATION
1kk8	SCALLOP MYOSIN (S1-ADP-BeFx) IN THE ACTIN-DETACHED CONFORMATION
1kqm	SCALLOP MYOSIN S1-AMPPNP IN THE ACTIN-DETACHED CONFORMATION
1kwo	SCALLOP MYOSIN S1-ATPgammaS-p-PDM IN THE ACTIN-DETACHED CONFORMATION
1l2o	SCALLOP MYOSIN S1-ADP-p-PDM IN THE ACTIN-DETACHED CONFORMATION
1m45	CRYSTAL STRUCTURE OF MLC1P BOUND TO IQ2 OF MYO2P, A CLASS V MYOSIN
1m8q	Molecular Models of Averaged Rigor Crossbridges from Tomograms of Insect Flight Muscle
1mvw	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1n2d	Ternary complex of MLC1P bound to IQ2 and IQ3 of Myo2p, a class V myosin
1o18	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o19	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o1a	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o1b	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o1c	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o1d	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o1e	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o1f	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1o1g	MOLECULAR MODELS OF AVERAGED RIGOR CROSSBRIDGES FROM TOMOGRAMS OF INSECT FLIGHT MUSCLE
1oe9	Crystal structure of Myosin V nucleotide-free
1qvi	Crystal structure of scallop myosin S1 in the pre-power stroke state to 2.6 Angstrom resolution: flexibility and function in the head
1s5g	Structure of Scallop myosin S1 reveals a novel nucleotide conformation
1scm	STRUCTURE OF THE REGULATORY DOMAIN OF SCALLOP MYOSIN AT 2.8 ANGSTROMS RESOLUTION
1sr6	Structure of nucleotide-free scallop myosin S1
1w7i	Crystal Structure Of Myosin V Motor Without nucleotide soaked in 10 mM MgADP
1w7j	Crystal Structure Of Myosin V Motor With Essential Light Chain + ADP-BeFx - Near Rigor
1wdc	SCALLOP MYOSIN REGULATORY DOMAIN
2bki	Myosin VI nucleotide-free (MDinsert2-IQ) crystal structure
2bl0	Physarum polycephalum myosin II regulatory domain
2dfs	3-D structure of Myosin-V inhibited state
2ec6	Placopecten Striated Muscle Myosin II
2ix7	Structure of apo-calmodulin bound to unconventional myosin V
2kxw	Structure of the C-domain Fragment of apo Calmodulin Bound to the IQ motif of Nav1.2
2l53	Solution NMR Structure of apo-calmodulin in complex with the IQ motif of Human Cardiac Sodium Channel NaV1.5
2m5e	2M5E
2mys	MYOSIN SUBFRAGMENT-1, ALPHA CARBON COORDINATES ONLY FOR THE TWO LIGHT CHAINS
2os8	Rigor-like structures of muscle myosins reveal key mechanical elements in the transduction pathways of this allosteric motor
2otg	Rigor-like structures of muscle myosins reveal key mechanical elements in the transduction pathways of this allosteric motor
2w4a	Isometrically contracting insect asynchronous flight muscle
2w4g	Isometrically contracting insect asynchronous flight muscle quick frozen after a quick stretch step
2w4h	Isometrically contracting insect asynchronous flight muscle quick frozen after a quick release step
2w4t	Isometrically contracting insect asynchronous flight muscle
2w4v	Isometrically contracting insect asynchronous flight muscle quick frozen after a quick release step
2w4w	Isometrically contracting insect asynchronous flight muscle quick frozen after a quick stretch step
3dtp	Tarantula heavy meromyosin obtained by flexible docking to Tarantula muscle thick filament Cryo-EM 3D-MAP
3gn4	Myosin lever arm
3i5f	Crystal structure of squid MG.ADP myosin S1
3i5g	Crystal structure of rigor-like squid myosin S1
3i5h	The crystal structure of rigor like squid myosin S1 in the absence of nucleotide
3i5i	The crystal structure of squid myosin S1 in the presence of SO4 2-
3j04	EM structure of the heavy meromyosin subfragment of Chick smooth muscle Myosin with regulatory light chain in phosphorylated state
3jax	3JAX
3jbh	3JBH
3jtd	Calcium-free Scallop Myosin Regulatory Domain with ELC-D19A Point Mutation
3jvt	Calcium-bound Scallop Myosin Regulatory Domain (Lever Arm) with Reconstituted Complete Light Chains
3pn7	Visualizing new hinges and a potential major source of compliance in the lever arm of myosin
3ts5	Crystal Structure of a Light Chain Domain of Scallop Smooth Muscle Myosin
3tuy	Phosphorylated Light Chain Domain of Scallop smooth Muscle Myosin
3wfn	Crystal Structure of Nav1.6 IQ motif in complex with apo-CaM
4byf	Crystal structure of human Myosin 1c in complex with calmodulin in the pre-power stroke state
4dck	Crystal structure of the C-terminus of voltage-gated sodium channel in complex with FGF13 and CaM
4e50	Calmodulin and Ng peptide complex
4e53	Calmodulin and Nm peptide complex
4jpz	Voltage-gated sodium channel 1.2 C-terminal domain in complex with FGF13U and Ca2+/calmodulin
4jq0	Voltage-gated sodium channel 1.5 C-terminal domain in complex with FGF12B and Ca2+/calmodulin
4l79	Crystal Structure of nucleotide-free Myosin 1b residues 1-728 with bound Calmodulin
4lzx	Complex of IQCG and Ca2+-free CaM
4m1l	Complex of IQCG and Ca2+-bound CaM
4ovn	4OVN
4qbd	4QBD
4r8g	4R8G
4zlk	4ZLK
5i0i	5I0I

Links (links to other resources describing this domain)

• INTERPRO: IPR000048