ERAB contains a putative noncleavable signal peptide

The 42-residue amyloid beta protein (A beta 42) has been shown to be toxic to neurons and is believed to play a key causative role in Alzheimer's disease (AD). A search for A beta binding proteins that can mediate its toxicity resulted in the identification of the endoplasmic-reticulum (ER) associated A beta binding protein (ERAB) which was also shown to be involved in AP induced apoptosis. The primary report indicated that a signal sequence is absent in ERAB suggesting that it is bound to the cytoplasmic aspect of cellular membranes. A beta is generated in the lumen of secretory organelles and released into the medium resulting in its separation from ERAB by a membrane barrier. After computer analysis of the ERAB sequence, we have detected a putative signal peptide that can direct the protein into the secretory pathway. This signal sequence was found in human, rodent, and bovine ERAB suggesting that it is a type II integral membrane protein in vertebrates. This topology can explain the binding of A beta to ERAB. Our finding that an integral membrane form of ERAB can bind to A beta in the lumen of transport vesicles and other cytoplasmic receptors provides a basis for understanding its role in AD. (C) 1998 Academic Press.