Structures and metal-ion-binding properties of the Ca2+-binding helix-loop-helix EF-hand motifs.
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.
Gifford
Jessica L
JL
Structural Biology Research Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada T2N 1N4.
Walsh
Michael P
MP
Vogel
Hans J
HJ
D000595:Amino Acid Sequence; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D020832:EF Hand Motifs / Q000502:physiology*; D008274:Magnesium / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D025941:Protein Interaction Mapping; D064030:S100 Calcium Binding Protein G / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
D064026:Calbindins; D002147:Calmodulin; D064030:S100 Calcium Binding Protein G; D008274:Magnesium; D002118:Calcium