EF hand

The EF hand is a helix-turn-helix structural domain found in a large family of calcium-binding proteins. It consists of two alpha helices positioned roughly perpendicular to one another and linked by a short loop region (usually about 12 amino acids) that usually binds calcium ions. 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. EF hands also appear in each structural domain of the signaling protein calmodulin and in the muscle protein troponin-C.

Binding site
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 the stabilizes the two helices.

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).

Classification
The EF-hands can be divided into two classes: signaling proteins and 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.

Subfamilies

 * EPS15 homology (EH) domain

Human proteins containing this domain
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;  LCP1;      MACF1;     MRLC2;     MRLC3;     MST133; MYL1;     MYL2;      MYL5;      MYL6B;     MYL7;      MYL9;      MYLC2PL;   MYLPF; NCALD;    NIN;       NKD1;      NKD2;      NLP;       NOX5;      NUCB1;     NUCB2;     OCM;       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;      SDF4;      SLC25A12;  SLC25A13;  SLC25A23; SLC25A24; SLC25A25;  SPATA21;   SPTA1;     SPTAN1;    SRI;       TBC1D9;    TBC1D9B; TCHH;     TESC;      TNNC1;     TNNC2;     USP32;     VSNL1;     ZZEF1;