The Role of ATP8A1‐CDC50a on Learning Deficits

Abstract

ATP8A1-CDC50a is a Type 4 P-type ATPase protein composed of two subunit proteins, the ATP8A1 section and the CDC50a section, connected by heterodimerization. Originally found in red blood cells, the ATP8A1 section was the first identified member of the P4-ATPase family and works as a flippase that uses the energy from ATP hydrolysis to translocate phospholipids from the outer to inner leaflet of eukaryotic cellular membranes in order to maintain phospholipid asymmetry necessary for membrane trafficking, membrane biogenesis, apoptosis, and signaling pathways. CDC50 proteins are common binding partners of the human class-1 P-ATPases to form heteromeric complexes which, in the case of ATP8A1-CDC50a, associate with and recruit P4-ATPase ATP8A1 to the plasma membrane. The CDC50a section functions as a chaperone protein to ATP8A1 and facilitates the proper folding and flippase activity. Mutations in some P4-ATPases cause inherited genetic diseases such as with ATP8A1-CDC50a and ATP8A2-CDC50, two closely related proteins in the P4-ATPase family, which can cause neurological disorders and learning deficits; however, only ATP8A2-CDC50 mutations are linked to severe neurological defects, whereas there is no clear disease associations linked to ATP8A1-CDC50a. Despite this, overexpression of CDC50a leads to extensive cell spreading and enhanced cell migration while a deficiency of either CDC50A or ATP8A1 may lead to severe defects in the formation of membrane ruffles, in turn inhibiting cell migration. The Walton SMART team has designed a 3D model of ATP8A1-CDC50a to investigate the relationship between its structure and function.