Immunocytochemical localization and crystal structure of human frequenin (neuronal calcium sensor 1)

Frequenin, a member of a large family of myristoyl-switch calcium-binding p roteins, functions as a calcium-ion sensor to modulate synaptic activity an d secretion. We show that human frequenin colocalizes with ARF1 GTPase in C OS-7 cells and occurs in similar cellular compartments as the phosphatidyli nositol-4-OH kinase PI4K beta, the mammalian homolog of the yeast kinase PI K1. In addition, the crystal structure of unmyristoylated, calcium-bound hu man frequenin has been determined and refined to 1.9 Angstrom resolution. T he overall fold of frequenin resembles those of neurocalcin and the photore ceptor, recoverin, of the same family, with two pairs of calcium-binding EF hands and three bound calcium ions. Despite the similarities, however, fre quenin displays significant structural differences. A large conformational shift of the C-terminal region creates a wide hydrophobic crevice at the su rface of frequenin. This crevice, which is unique to frequenin and distinct from the myristoyl binding box of recoverin, may accommodate a yet unknown protein ligand.