Structure and Function of SERCA and SPCA
A hypothetical model of the tertiary structure of SERCA has been proposed, based on biochemical and structural information. The molecule is divided into three major parts: the 'cytoplasmic headpiece', a connecting 'stalk domain' and the 'transmembrane domain' (Fig. 5). More than half the total mass of the molecule is exposed on the cytoplasmic surface of the membrane in the cytoplasmic headpiece and this contains the phosphorylation and nucleotide binding domains that form the active site of ATP hydrolysis. The 10 hydrophobic transmembrane helices in the transmembrane domain anchor the molecule to the lipid bilayer, contain the Ca2+ binding sites and form a transmembrane channel for the passage of Ca2+.
The predicted secondary structure of SERCA2a consists of 10 transmembrane domains with a tetrapeptide tail that is located in the cytoplasm. SERCA2b has a much longer tail that extends into the lumen of the endoplasmic reticulum rather than terminating in the cytoplasm. This extended tail in SERCA2b may serve as an 11th transmembrane domain. Differences in the C-terminal region of SERCA2b, especially the last 12 amino acids, are responsible for functional differences in SERCA2a and SERCA2b. We have shown that mutations affecting the extended tail of SERCA2b are sufficient to cause Darier's disease.
Ca2+ binds to two high-affinity sites in the transmembrane domain that are formed by the precise juxtaposition of three helices. These sites are accessible from the cytoplasm, but not from the lumen. Phosphorylation of the enzyme by ATP initiates a series of structural changes that, through long-range interactions, change the conformation of the transmembrane helices so that access of Ca2+ to the cytoplasm is lost. Access to the lumen is gained and the affinity of binding sites for Ca2+ is reduced, releasing Ca2+ into the lumen.
The structure of the SPCA family is thought to be similar to the SERCA family, but unlike SERCA, which transports two Ca2+ ions per ATP hydrolysed, the SPCA family is postulated to contain only a single Ca2+ binding site and transport a single Ca2+ or Mn2+ ion.
The British Journal of Dermatology. 2004;150(5) © 2004 Blackwell Publishing
Cite this: Calcium Pumps and Keratinocytes: Lessons From Darier's Disease and Hailey-Hailey Disease - Medscape - May 01, 2004.