J. Rossjohn et al., Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein, NAT ST BIOL, 6(4), 1999, pp. 327-331
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.