The role of calcium‐binding proteins in the control of transcription: structure to function

Abstract

Transcriptional regulation is coupled with numerous intracellular signaling processes often mediated by second messengers. Now, growing evidence points to the importance of Ca(2+), one of the most versatile second messengers, in activating or inhibiting gene transcription through actions frequently mediated by members of the EF-hand superfamily of Ca(2+)-binding proteins. Calmodulin and calcineurin, representative members of this EF-hand superfamily, indirectly regulate transcription through phosphorylation/dephosphorylation of transcription factors in response to a Ca(2+) increase in the cell. Recently, a novel EF-hand Ca(2+)-binding protein called DREAM has been found to interact with regulatory sequences of DNA, thereby acting as a direct regulator of transcription. Finally, S100B, a dimeric EF-hand Ca(2+)-binding protein, interacts with the tumor suppressor p53 and controls its transcriptional activity. In light of the structural studies reported to date, this review provides an overview of the structural basis of EF-hand Ca(2+)-binding proteins linked with transcriptional regulation.

Binding of trifluoperazine to apocalmodulin revealed by a combination of small-angle X-ray scattering and nuclear magnetic resonance

“…We proposed that Ca 2+ CaM complexed with mastoparan adopts a compact globular shape by bending of the domain linker (Matsushima et al, 1989). This was confirmed by crystallographic and nuclear magnetic resonance (NMR) studies on various target Ca 2+ CaM-binding proteins including MLCK, CaMdependent protein kinase (CaMK) and myristoylated alanine-rich Ckinase substrate (MARCKS) (reviewed in Ikura et al, 2002;Yamniuk & Vogel, 2004;Ikura & Ames, 2006). In contrast, although the interactions of apoCaM have been studied with some target proteins such as neurogranin, cyclic nucleotide phosphodiesterase (PDE), small conductance Ca 2+ -activated K + channel (SK channel), voltagegated sodium channel, MLCK and myosin V (Cui et al, 2003;Yuan et al, 1999;Mori et al, 2003;Tsvetkov et al, 1999;Hill et al, 2000;Bayley et al, 2003;Akyol et al, 2004;Tang et al, 2003;Jin et al, 2005;Houdusse et al, 2006), structural studies are very rare (Izumi et al, 2001;Schumacher et al, 2004).…”

“…An IQ or IQ-like domain often mediates Ca 2+ -independent CaM binding (reviewed in Jurado et al, 1999;Bä hler & Rhoads, 2002). Ca 2+ -dependent target proteins primarily contain domains that can be classified into motifs based upon variations on the basic amphiphilic -helix domain involving conserved hydrophobic residues at positions 1-10, 1-14 or 1-16 (reviewed in Rhoads & Friedberg, 1997;Ikura et al, 2002;Yamniuk & Vogel, 2004). SAXS measurements of Ca 2+ CaM with an amphiphilic peptide such as mastoparan or mellitin and a peptide from myosin light chain kinase (MLCK) showed large conformational changes of Ca 2+ CaM (Matsushima et al, 1989;Heidorn et al, 1989;Kataoka et al, 1989).…”

Calcium influx and DREAM protein are required for GnRH gene expression pulse activity

“…In many cases, the ability of Ca 2+ to initiate a cellular response depends on proteins that first bind calcium and then interact with other regulatory components of the transcriptional machinery. Among these proteins, calretinin, calcineurin and calmodulin received a great deal of attention (for review see Ikura et al, 2002). Recently, a novel calcium binding protein capable of interacting with components in both the cytoplasmic and nuclear compartments of the cell was identified in GT1-7 neurons .…”

Target recognition by calmodulin: the role of acid region contiguous to the calmodulin‐binding domain of calcineurin A

“…The structures of Ca 2þ / CaM complexed with a CaM-binding domain from target enzymes adopt a compact globular structure caused by the bending of the central linker [5][6][7]. Recently, however, an extended but not collapsed structure of CaM found in the complexes with a model peptide and the crystal of CaMregulated adenylate cyclase suggests that CaM should regulate target proteins with versatile ways [8,9]. Moreover, the structure of Ca 2þ -free CaM (apoCaM) remains unchanged upon binding the CaM-binding domain, except for the decrease of the flexibility of the central linker [10].…”