APP-BP1, a Novel Protein That Binds to the Carboxyl-terminal Region of the Amyloid Precursor Protein

Nienwen Chow,Julie R Korenberg,Xiao-Ning Chen,Rachael L Neve

doi:10.1074/jbc.271.19.11339

Abstract

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.

Highlights

␤-Amyloid protein precursors (APPs, 695–770 amino acids) are the source of the 39 – 43-amino acid ␤-amyloid (A␤) peptides that comprise diffuse and fibrillar deposits in the cerebral cortex and vasculature of Alzheimer’s disease brains
The glutathione S-transferase (GST)-APPC100His6 fusion protein was radiolabeled by phosphorylation with the catalytic subunit of cAMP-dependent protein kinase and was cleaved with thrombin to release amyloid precursor protein (APP)-C100His6 from the matrix-bound GST
A human cDNA encoding a 59-kDa protein was isolated by screening expression cDNA libraries with the radiolabeled carboxyl-terminal region of APP

Summary

Introduction

␤-Amyloid protein precursors (APPs, 695–770 amino acids) are the source of the 39 – 43-amino acid ␤-amyloid (A␤) peptides that comprise diffuse and fibrillar deposits in the cerebral cortex and vasculature of Alzheimer’s disease brains. APP is a cell surface protein with a large extracellular amino-terminal domain, a single transmembrane segment, and a short cytoplasmic tail. 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. The amino acid sequences of APP and APLPs are highly conserved, and the protein structures of APP and APLPs are similar. APLPs, like APP, are located on the cell surface They have a large extracellular amino-terminal domain, a single transmembrane region, and a short cytoplasmic tail. Only APP has the A␤ segment, whose amino terminus is extracellular and whose carboxyl terminus is within the cell membrane

Methods

Results

Conclusion