Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein

Amyloid precursor protein (APP) plays a central role in Alzheimer disease. A proteolytic-breakdown product of APP, called beta-amyloid, is a major com ponent of the diffuse and fibrillar deposits found in Alzheimer diseased br ains. The normal physiological role of APP remains largely unknown despite much work. A knowledge of its function will not only provide insights into the genesis of the disease but may also prove vital in the development of a n effective therapy. Here we describe the 1.8 Angstrom resolution crystal s tructure of the N-terminal, heparin-binding domain of APP (residues 28-123) , which is responsible, among other things, for stimulation of neurite outg rowth. The structure reveals a highly charged basic surface that may intera ct with glycosaminoglycans in the brain and an abutting hydrophobic surface that is proposed to play an important functional role such as dimerization or ligand binding. Structural similarities with cysteine-rich growth facto rs, taken together with its known growth-promoting properties, suggests the APP N-terminal domain could function as a growth factor in vivo.