Summary: EF-hand domain
This is the Wikipedia entry entitled "EF hand". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at email@example.com and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
EF hand Edit Wikipedia article
Structure of the recombinant Paramecium tetraurelia calmodulin.
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, PDB 1gcg) 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.
- EPS15 homology (EH) domain – IPR000261
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 Biol. Crystallogr. 50 (Pt 1): 50–63. doi:10.1107/S0907444993007991. PMID 15299476.
- 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. doi:10.1371/journal.pone.0079002. PMC 3823939. PMID 24244400.
- 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. doi:10.1146/annurev.bb.23.060194.002353. PMID 7919790.
- 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. doi:10.1002/prot.21139. PMID 16981205.
- Zhou Y, Frey TK, Yang JJ (July 2009). "Viral calciomics: interplays between Ca2+ and virus". Cell Calcium 46 (1): 1–17. doi:10.1016/j.ceca.2009.05.005. PMID 19535138.
- 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. doi:10.1007/BF00162998. PMID 1602495.
- 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. doi:10.1016/0014-5793(90)81214-9. PMID 2401372.
- Finn BE, Forsén S (January 1995). "The evolving model of calmodulin structure, function and activation". Structure 3 (1): 7–11. doi:10.1016/S0969-2126(01)00130-7. PMID 7743133.
- 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. doi:10.1016/j.cell.2008.08.006. PMID 18854159.
- 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. doi:10.1110/ps.33302. PMC 2373453. PMID 11790829.
- Eukaryotic Linear Motif resource motif class LIG_EH_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. Retrieved 2009-08-29. "prediction server for EF-hand calcium binding proteins"
EF-hand domain Provide feedback
No Pfam abstract.
Internal database links
|Similarity to PfamA using HHSearch:||EF-hand_1 SPARC_Ca_bdg EF-hand_4 EF-hand_5 EF-hand_7 EF-hand_7 EF-hand_8 EF-hand_10|
External database links
This tab holds annotation information from the InterPro database.
No InterPro data for this Pfam family.
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Loading domain graphics...
The EF hand is a calcium binding domain found in a wide variety of proteins .
The clan contains the following 16 members:Caleosin Dockerin_1 EF-hand_1 EF-hand_10 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 EFhand_Ca_insen S_100 SPARC_Ca_bdg
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
If you find these logos useful in your own work, please consider citing the following article:
Note: You can also download the data file for the tree.
Curation and family details
|Number in seed:||793|
|Number in full:||5737|
|Average length of the domain:||32.40 aa|
|Average identity of full alignment:||24 %|
|Average coverage of the sequence by the domain:||8.28 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||1|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
How the sunburst is generated
Colouring and labels
Anomalies in the taxonomy tree
Missing taxonomic levels
Unmapped species names
Too many species/sequences
The tree shows the occurrence of this domain across different species. More...
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
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 127 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 seqence.
Loading structure mapping...