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 component of the diffuse and fibrillar deposits found in Alzheimer diseased brains. 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 an effective therapy. Here we describe the 1.8 A resolution crystal structure of the N-terminal, heparin-binding domain of APP (residues 28-123), which is responsible, among other things, for stimulation of neurite outgrowth. The structure reveals a highly charged basic surface that may interact 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 factors, taken together with its known growth-promoting properties, suggests the APP N-terminal domain could function as a growth factor in vivo.
Rossjohn
J
J
The Ian Potter Foundation Protein Crystallography Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
Cappai
R
R
Feil
S C
SC
Henry
A
A
McKinstry
W J
WJ
Galatis
D
D
Hesse
L
L
Multhaup
G
G
Beyreuther
K
K
Masters
C L
CL
Parker
M W
MW
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006133:Growth Substances / Q000737:chemistry; D006493:Heparin / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid
D016564:Amyloid beta-Protein Precursor; D006133:Growth Substances; D010446:Peptide Fragments; D017228:Hepatocyte Growth Factor; D006493:Heparin