The amyloid precursor-like protein 2 associates with the major histocompatibility complex class I molecule Kd

Amyloid precursor-like protein 2 (APLP2) is a member of a protein family related to the amyloid precursor protein, which is implicated in Alzheimer's disease. Little is known about the physiological function of this protein family. The adenovirus E3/19K protein binds to major histocompatibility complex (MHC) class I antigens in the endoplasmic reticulum, thereby preventing their transport to the cell surface. In cells coexpressing E3/19K and the MHC K-d molecule, K-d is associated with E3/19K and two cellular protein species with masses of 100 and 110 kDa, termed p100/110, Interestingly, p100/110 are released from the complex upon the addition of K-d-binding peptides, suggesting a role for these proteins in peptide transfer to MHC molecules. Here we demonstrate by microsequencing, reactivity with APLP2-specific antibodies, and comparison of biochemical parameters that p100/110 is identical to human APLP2, We further show that the APLP2/K-d association does not require the physical presence of E3/19K. Thus, APLP2 exhibits an intrinsic affinity for the MHC K-d molecule. Similar to the binding of MHC molecules to the transporter associated with antigen processing, complex formation between APLP2 and K-d strictly depends upon the presence of beta(2)-microglobulin. Conditions that prolong the residency of K-d in the endoplasmic reticulum lead to a profound increase of the association and a drastic reduction of APLP2 transport. Therefore, this unexpected interplay between these unrelated molecules may have implications for both MHC antigen and APLP2 function.