Summary: EF-hand domain
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EF hand Edit Wikipedia article
The EF-hand motif contains a helix-loop-helix topology, much like the spread thumb and forefinger of the human hand, in which the Ca2+ ions are coordinated by ligands within the loop. The motif takes its name from traditional nomenclature used in describing the protein parvalbumin, which contains three such motifs and is probably involved in muscle relaxation via its calcium-binding activity.
The EF-hand consists of two alpha helices linked by a short loop region (usually about 12 amino acids) that usually binds calcium ions. EF-hands also appear in each structural domain of the signaling protein calmodulin and in the muscle protein troponin-C.
Calcium ion binding site
- The calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand).
- The calcium ion is bound by both protein backbone atoms and by amino acid side chains, specifically those of the acidic amino acid residues aspartate and glutamate. These residues are negatively charged and will make a charge-interaction with the positively charged calcium ion. The EF hand motif was among the first structural motifs whose sequence requirements were analyzed in detail. Five of the loop residues bind calcium and thus have a strong preference for oxygen-containing side chains, especially aspartate and glutamate. The sixth residue in the loop is necessarily glycine due to the conformational requirements of the backbone. The remaining residues are typically hydrophobic and form a hydrophobic core that binds and stabilizes the two helices.
- Upon binding to Ca2+, this motif may undergo conformational changes that enable Ca2+-regulated functions as seen in Ca2+ effectors such as calmodulin (CaM) and troponin C (TnC) and Ca2+ buffers such as calreticulin and calbindin D9k. While the majority of the known EF-hand Calcium-binding proteins (CaBPs) contain paired EF-hand motifs, CaBP’s with single EF hands have also been discovered in both bacteria and eukaryotes. In addition, "EF-hand-like motifs" have been found in a number of bacteria. Although the coordination properties remain similar with the canonical 29-residue helix-loop-helix EF-hand motif, the EF-hand-like motifs differ from EF-hands in that they contain deviations in the secondary structure of the flanking sequences and/or variation in the length of the Ca2+-coordinating loop.
- Pattern (motif signature) search is one of the most straightforward ways to predict continuous EF-hand Ca2+-binding sites in proteins. Based on the sequence alignment results of canonical EF-hand motifs, especially the conserved side chains directly involved in Ca2+ binding, a pattern PS00018 has been generated to predict canonical EF-hand sites. A prediction servers may be found in the external links section.
- Since the delineation of the EF-hand motif in 1973, the family of EF-hand proteins has expanded to include at least 66 subfamilies thus far. EF-hand motifs are divided into two major groups:
- Canonical EF-hands as seen in calmodulin (CaM) and the prokaryotic CaM-like protein calerythrin. The 12-residue canonical EF-hand loop binds Ca2+ mainly via sidechain carboxylates or carbonyls (loop sequence positions 1, 3, 5, 12). The residue at the –X axis coordinates the Ca2+ ion through a bridged water molecule. The EF-hand loop has a bidentate ligand (Glu or Asp) at axis –Z.
- Pseudo EF-hands exclusively found in the N-termini of S100 and S100-like proteins. The 14-residue pseudo EF-hand loop chelates Ca2+ primarily via backbone carbonyls (positions 1, 4, 6, 9).
- EF-hand-like proteins with diversified flanking structural elements around the Ca2+-binding loop have been reported in bacteria and viruses. These prokaryotic EF-hand-like proteins are widely implicated in Ca2+ signaling and homeostasis in bacteria. They contain flexible lengths of Ca2+-binding loops that differ from the EF-hand motifs. However, their coordination properties resemble classical EF-hand motifs.
- For example, the semi-continuous Ca2+-binding site in D-galactose-binding protein (GBP) contains a nine-residue loop. The Ca2+ ion is coordinated by seven protein oxygen atoms, five of which are from the loop mimicking the canonical EF-loop whereas the other two are from the carboxylate group of a distant Glu.
- Another example is a novel domain named Excalibur (extracellular Ca2+-binding region) isolated from Bacillus subtilis. This domain has a conserved 10-residue Ca2+-binding loop strikingly similar to the canonical 12-residue EF-hand loop.
- The diversity of the structure of the flanking region is illustrated by the discovery of EF-hand-like domains in bacterial proteins. For example, a helix-loop-strand instead of the helix-loop-helix structure is in periplasmic galactose-binding protein (Salmonella typhimurium, ) or alginate-binding protein (Sphingomonas sp., ); the entering helix is missing in protective antigen (Bacillus anthracis, ) or dockerin (Clostridium thermocellum, ).
- Among all the structures reported to date, the majority of EF-hand motifs are paired either between two canonical or one pseudo and one canonical motifs. For proteins with odd numbers of EF-hands, such as the penta-EF-hand calpain, EF-hand motifs were coupled through homo- or hetero-dimerization. The recently-identified EF-hand containing ER Ca2+ sensor protein, stromal interaction molecule 1 and 2 (STIM1, STIM2), has been shown to contain a Ca2+-binding canonical EF-hand motif that pairs with an immediate, downstream atypical "hidden" non-Ca2+-binding EF-hand. Single EF-hand motifs can serve as protein-docking modules: for example, the single EF hand in the NKD1 and NKD2 proteins binds the Dishevelled (DVL1, DVL2, DVL3) proteins.
- Functionally, the EF-hands can be divided into two classes: 1) signaling proteins and 2) buffering/transport proteins. The first group is the largest and includes the most well-known members of the family such as calmodulin, troponin C and S100B. These proteins typically undergo a calcium-dependent conformational change which opens a target binding site. The latter group is represented by calbindin D9k and do not undergo calcium dependent conformational changes.
Aequorin is a calcium binding protein (CaBP) isolated from the coelenterate Aequorea victoria. Aequorin belongs to the EF-hand family of CaBPs, with EF-hand loops that are closely related to CaBPs in mammals. In addition, aequorin has been used for years as an indicator of Ca2+ and has been shown to be safe and well tolerated by cells. Aequorin is made up of two components – the calcium binding component apoaequorin (AQ) and the chemiluminescent molecule coelenterazine. The AQ portion of this protein contains the EF-hand calcium binding domains.
Humans proteins containing this domain include:
- ACTN1; ACTN2; ACTN3; ACTN4; APBA2BP; AYTL1; AYTL2
- C14orf143; CABP1; CABP2; CABP3; CABP4; CABP5; CABP7; CALB1; CALB2; CALM2; CALM3; CALML3; CALML4; CALML5; CALML6; CALN1; CALU; CAPN1; CAPN11; CAPN2; CAPN3; CAPN9; CAPNS1; CAPNS2; CAPS; CAPS2; CAPSL; CBARA1; CETN1; CETN2; CETN3; CHP; CHP2; CIB1; CIB2; CIB3; CIB4; CRNN
- DGKA; DGKB; DGKG; DST; DUOX1; DUOX2
- EFCAB1; EFCAB2; EFCAB4A; EFCAB4B; EFCAB6; EFCBP1; EFCBP2; EFHA1; EFHA2; EFHB; EFHC1; EFHD1; EFHD2; EPS15; EPS15L1
- FKBP10; FKBP14; FKBP7; FKBP9; FKBP9L; FREQ; FSTL1; FSTL5
- GCA; GPD2; GUCA1A; GUCA1B; GUCA1C
- hippocalcin; HPCAL1; HPCAL4; HZGJ
- IFPS; ITSN1; ITSN2; KCNIP1; KCNIP2; KCNIP3; KCNIP4; KIAA1799
- MACF1; MRLC2; MRLC3; MST133; MYL1; MYL2; MYL5; MYL6B; MYL7; MYL9; MYLC2PL; MYLPF
- NCALD; NIN; NKD1; NKD2; NLP; NOX5; NUCB1; NUCB2
- PDCD6; PEF1; PKD2; PLCD1; PLCD4; PLCH1; PLCH2; PLS1; PLS3; PP1187; PPEF1; PPEF2; PPP3R1; PPP3R2; PRKCSH; PVALB
- RAB11FIP3; RASEF; RASGRP; RASGRP1; RASGRP2; RASGRP3; RCN1; RCN2; RCN3; RCV1; RCVRN; REPS1; RHBDL3; RHOT1; RHOT2; RPTN; RYR2; RYR3
- S100A1; S100A11; S100A12; S100A6; S100A8; S100A9; S100B; S100G; S100Z; SCAMC-2; SCGN; SCN5A; SDF4; SLC25A12; SLC25A13; SLC25A23; SLC25A24; SLC25A25; SPATA21; SPTA1; SPTAN1; SRI
- TBC1D9; TBC1D9B; TCHH; TESC; TNNC1; TNNC2
- Another distinct calcium-binding motif composed of alpha helices is the dockerin domain.
- Ban C, Ramakrishnan B, Ling KY, Kung C, Sundaralingam M (January 1994). "Structure of the recombinant Paramecium tetraurelia calmodulin at 1.68 A resolution". Acta Crystallogr. D. 50 (Pt 1): 50–63. PMID 15299476. doi:10.1107/S0907444993007991.
- Detert JA, Adams EL, Lescher JD, Lyons JA, Moyer JR (2013). "Pretreatment with Apoaequorin Protects Hippocampal CA1 Neurons from Oxygen-Glucose Deprivation". PLoS ONE. 8 (11): e79002. PMC . PMID 24244400. doi:10.1371/journal.pone.0079002.
- Branden C, Tooze J (1999). "Chapter 2: Motifs of protein structure". Introduction to Protein Structure. New York: Garland Pub. pp. 24–25. ISBN 0-8153-2305-0.
- Nakayama S, Kretsinger RH (1994). "Evolution of the EF-hand family of proteins". Annu Rev Biophys Biomol Struct. 23: 473–507. PMID 7919790. doi:10.1146/annurev.bb.23.060194.002353.
- Zhou Y, Yang W, Kirberger M, Lee HW, Ayalasomayajula G, Yang JJ (November 2006). "Prediction of EF-hand calcium-binding proteins and analysis of bacterial EF-hand proteins". Proteins. 65 (3): 643–55. PMID 16981205. doi:10.1002/prot.21139.
- Zhou Y, Frey TK, Yang JJ (July 2009). "Viral calciomics: interplays between Ca2+ and virus". Cell Calcium. 46 (1): 1–17. PMC . PMID 19535138. doi:10.1016/j.ceca.2009.05.005.
- Nakayama S, Moncrief ND, Kretsinger RH (May 1992). "Evolution of EF-hand calcium-modulated proteins. II. Domains of several subfamilies have diverse evolutionary histories". J. Mol. Evol. 34 (5): 416–48. PMID 1602495. doi:10.1007/BF00162998.
- Hogue CW, MacManus JP, Banville D, Szabo AG (July 1992). "Comparison of terbium (III) luminescence enhancement in mutants of EF hand calcium binding proteins". J. Biol. Chem. 267 (19): 13340–7. PMID 1618836.
- Bairoch A, Cox JA (September 1990). "EF-hand motifs in inositol phospholipid-specific phospholipase C". FEBS Lett. 269 (2): 454–6. PMID 2401372. doi:10.1016/0014-5793(90)81214-9.
- Finn BE, Forsén S (January 1995). "The evolving model of calmodulin structure, function and activation". Structure. 3 (1): 7–11. PMID 7743133. doi:10.1016/S0969-2126(01)00130-7.
- Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M (October 2008). "Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry". Cell. 135 (1): 110–22. PMID 18854159. doi:10.1016/j.cell.2008.08.006.
- Nelson MR, Thulin E, Fagan PA, Forsén S, Chazin WJ (February 2002). "The EF-hand domain: a globally cooperative structural unit". Protein Sci. 11 (2): 198–205. PMC . PMID 11790829. doi:10.1110/ps.33302.
- Eukaryotic Linear Motif resource motif class LIG_EH_1
- Eukaryotic Linear Motif resource motif class LIG_IQ
- Eukaryotic Linear Motif resource motif class DOC_PP2B_LxvP_1
- Eukaryotic Linear Motif resource motif class LIG_IQ
- Nelson M, Chazin W. "EF-Hand Calcium-Binding Proteins Data Library". Vanderbilt University. Retrieved 2009-08-29.
- Haiech J. "EF-hand protein database (EF-handome)". European Calcium Society and the Université Libre de Bruxelles. Retrieved 2009-08-29.
upon request to firstname.lastname@example.org
- Yang J. "Calciomics". Georgia State University. Archived from the original on 2009-10-12. Retrieved 2009-08-29.
prediction server for EF-hand calcium binding proteins
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
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Internal database links
|SCOOP:||Caleosin Dockerin_1 DUF1103 DUF5580 EF-hand_1 EF-hand_10 EF-hand_11 EF-hand_4 EF-hand_5 EF-hand_7 EF-hand_8 EF-hand_9 EFhand_Ca_insen Pkinase Pro_dh SPARC_Ca_bdg TerB|
|Similarity to PfamA using HHSearch:||EF-hand_1 EF-hand_11 SPARC_Ca_bdg EF-hand_4 EF-hand_5 EF-hand_7 EF-hand_7 EF-hand_8 EF-hand_10|
This tab holds annotation information from the InterPro database.
InterPro entry IPR002048Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand. This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue alpha-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand). 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 [PUBMED:9228939,PUBMED:8848832,PUBMED:7553064,PUBMED:7656053,PUBMED:10591109]
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||calcium ion binding (GO:0005509)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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The EF hand is a calcium binding domain found in a wide variety of proteins .
The clan contains the following 31 members:Ca_chan_IQ Caleosin Cbl_N2 Cullin_binding DAG_kinase_N Dockerin_1 DUF5596 EF-hand_1 EF-hand_10 EF-hand_11 EF-hand_12 EF-hand_13 EF-hand_14 EF-hand_2 EF-hand_3 EF-hand_4 EF-hand_5 EF-hand_6 EF-hand_7 EF-hand_8 EF-hand_9 EF-hand_like EF_assoc_2 EFhand_Ca_insen Internalin_N IQ IQCJ-SCHIP1 NADPH_Ox p25-alpha S_100 SPARC_Ca_bdg
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Number in seed:||580|
|Number in full:||5750|
|Average length of the domain:||31.80 aa|
|Average identity of full alignment:||31 %|
|Average coverage of the sequence by the domain:||10.28 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||6|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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There are 11 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the EF-hand_6 domain has been found. There are 135 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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