beta-Amyloid protein precursors (APPs, 695-770 amino acids) are the source of the 39-43 amino acid beta-amyloid (A beta) peptides that comprise diffuse and fibrillar deposits in the cerebral cortex and vasculature of Alzheimer's disease brains. A beta is thought to play a role in the pathogenesis of Alzheimer's disease, and, hence, considerable effort has been invested in defining the means by which A beta is generated from the APPs. Knowledge of the normal function of the APPs is sure to provide insights into the genesis and pathological persistence of A beta in Alzheimer's disease. APP is a cell surface protein with a large extracellular amino-terminal domain, a single transmembrane segment, and a short cytoplasmic tail. Its location and structural features characteristic of a receptor for signal transduction led us to search for potential effector proteins capable of binding and interacting with its cytoplasmic domain. Here, we report the cloning of a cDNA encoding one such protein. This ubiquitously expressed 59-kDa APP-binding protein, called APP-BP1, is 61% similar to a protein encoded by the Arabidopsis AXR1 gene, required for normal response to the hormone auxin, and is a relative of the ubiquitin activating enzyme E1.