ERAB CONTAINS A PUTATIVE NONCLEAVABLE SIGNAL PEPTIDE

The 42-residue amyloid beta protein (A beta 42) has been shown to be t oxic to neurons and is believed to play a key causative role in Alzhei mer's disease (AD). A search for A beta binding proteins that can medi ate its toxicity resulted in the identification of the endoplasmic-ret iculum (ER) associated A beta binding protein (ERAB) which was also sh own to be involved in AP induced apoptosis. The primary report indicat ed that a signal sequence is absent in ERAB suggesting that it is boun d to the cytoplasmic aspect of cellular membranes. A beta is generated in the lumen of secretory organelles and released into the medium res ulting in its separation from ERAB by a membrane barrier. After comput er analysis of the ERAB sequence, we have detected a putative signal p eptide that can direct the protein into the secretory pathway. This si gnal sequence was found in human, rodent, and bovine ERAB suggesting t hat it is a type II integral membrane protein in vertebrates. This top ology can explain the binding of A beta to ERAB. Our finding that an i ntegral membrane form of ERAB can bind to A beta in the lumen of trans port vesicles and other cytoplasmic receptors provides a basis for und erstanding its role in AD. (C) 1998 Academic Press.