Abstract
The ‘EF-hand’ Ca2+-binding motif plays an essential role in eukaryotic cellular signalling, and the proteins containing this motif constitute a large and functionally diverse family. The EF-hand is defined by its helix–loop–helix secondary structure as well as the ligands presented by the loop to bind the Ca2+ ion. The identity of these ligands is semi-conserved in the most common (the ‘canonical’) EF-hand; however, several non-canonical EF-hands exist that bind Ca2+ by a different co-ordination mechanism. EF-hands tend to occur in pairs, which form a discrete domain so that most family members have two, four or six EF-hands. This pairing also enables communication, and many EF-hands display positive co-operativity, thereby minimizing the Ca2+ signal required to reach protein saturation. The conformational effects of Ca2+ binding are varied, function-dependent and, in some cases, minimal, but can lead to the creation of a protein target interaction site or structure formation from a molten-globule apo state. EF-hand proteins exhibit various sensitivities to Ca2+, reflecting the intrinsic binding ability of the EF-hand as well as the degree of co-operativity in Ca2+ binding to paired EF-hands. Two additional factors can influence the ability of an EF-hand to bind Ca2+: selectivity over Mg2+ (a cation with very similar chemical properties to Ca2+ and with a cytoplasmic concentration several orders of magnitude higher) and interaction with a protein target. A structural approach is used in this review to examine the diversity of family members, and a biophysical perspective provides insight into the ability of the EF-hand motif to bind Ca2+ with a wide range of affinities.
- calbindin D9K
- calcium ions (Ca2+)
- calmodulin
- co-operativity
- EF-hand
- magnesium ions (Mg2+)
Abbreviations: ALG-2, apoptosis-linked gene-2; AtCBL2, Arabidopsis thaliana (thale cress) calcineurin B-like protein; CaBP, Ca2+-binding protein; CaM, calmodulin; cTnC, cardiac-muscle troponin C; CaVP, Ca2+ vector protein; CIB, Ca2+- and integrin-binding protein; EF1, EF-hand 1; EH, Eps15-homology; ELC, essential light chain; ER/SR, endoplasmic/sarcoplasmic reticulum; GCAP-1, guanylate cyclase activating protein-1; NCS, neuronal Ca2+- sensor; NCXs, Na+/Ca2+; PEF, penta-EF-hand; RLC, regulatory light chain; rmsd, root mean square deviation; SCPs, sarcoplasmic Ca2+-binding proteins; skMLCK, skeletal-muscle myosin light-chain kinase; sTnC, skeletal-muscle troponin C; TnI, troponin I; TR2C, calmodulin tryptic fragment containing Ca2+-binding sites 3 and 4; yCaM, yeast calmodulin
- © The Authors Journal compilation © 2007 Biochemical Society