Structure and Function of Calcium-Binding Proteins

Abstract

The large calcium gradient across the plasma membrane creates different environments for intra- and extracellular calcium-binding proteins. The latter are continuously surrounded by 10−3M Ca2+, which promotes activation or stabilization of certain proteases, nucleases, or lipases. Other proteins, such as those involved in blood clotting, contain polyelectrolyte regions that are composed of carboxyglutamic or phosphoserine moieties that allow them to interact with Ca2+. In contrast, intracellular calcium-binding proteins, such as calmodulin and troponin C, the trigger proteins for muscle contractions, need to respond to an increase in Ca2+ from 10−7 to 10−6M during cell activation. Evidence is presented that the pairwise arrangement of characteristic helix-loop-helix calcium-binding sites can result in the positive cooperative binding of Ca2+. This can be further promoted by the binding of ligands, drugs, or target proteins. Several drug binding sites on calmodulin are allosterically related and their localization on the unusual dumbbell structure of this molecule will be discussed.