There is more to amyloid precursor protein (APP) than the peptide for which it is named. At 40-42 amino acids, amyloid-β (Aβ) may attract the most attention, but the full protein is almost 20 times as large, with most of it protruding from the cell surface. While the extracellular expanse of APP may be its business end, relatively little is understood about what it does. Some evidence suggests that the protein forms dimers, which could be important for function, and a paper in this week’s PNAS supports that idea. Researchers led by Manuel Than at the Leibniz Institute for Age Research-Fritz Lipmann Institute, Jena, Germany, crystallized one part of the APP extracellular domain. Analysis of the crystal structure predicts that it, and by extrapolation APP itself, should form a dimer in the presence of heparin.
“It is now very probable that cellular signaling of APP indeed uses the well-established principle of receptor dimerization, and in the future, other biomolecules, in addition to heparin/heparan sulfate, may be found to influence the APP monomer/dimer equilibrium,” noted Mathias Gralle, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany, in an e-mail to ARF (see full comment below). Gralle was not involved in the work but has studied the three-dimensional structure of APP in solution (see Gralle et al., 2006).
Transmembrane proteins such as APP are notoriously difficult to crystallize. Researchers generally get around this by studying smaller pieces rather than the whole protein. First author Sven Dahms and colleagues focused on the E1 N-terminal region of APP comprising copper binding (CuBD) and growth factor-like domains (GFLDs). They obtained enough of the protein fragment for crystallization by expressing it in and purifying it from Escherichia coli. Analysis of the crystals showed that the two domains rigidly interact to form one folding unit (see image below). “The solved structure could have a strong impact on function, because it indicates the two domains cannot work independently,” Than told ARF. How function might be affected by this rigid structure remains to be seen.
3-D Structure of the E1 N-terminal Domain of APP
The CuBD (green) and the GFLD (blue) form distinct folds connected by an interdomain linker (red). Dark colors represent α helices and lighter colors β-sheets. Disulphide bonds are shown as gold spheres. Image credit: Manuel Than, Leibniz Institute for Age Research-Fritz Lipmann Institute
The analysis also indicates that two E1 fragments can come together to form a dimer in the presence of heparin, which is known to bind APP. The protein dimer interface comprises positively charged amino acid side chains that are held in place by the negatively charged heparin. This would likely affect the whole structure of APP because “if E1 comes together, then the whole molecule must come together,” said Than.
Interestingly, the researchers found that the stability of the rigid interdomain structure of the E1 monomer is pH dependent, being tighter at slightly acidic pH (~5.0). The researchers suggest that APP could form distinct conformations in different cellular and extracellular milieus.—Tom Fagan
- Gralle M, Oliveira CL, Guerreiro LH, McKinstry WJ, Galatis D, Masters CL, Cappai R, Parker MW, Ramos CH, Torriani I, Ferreira ST. Solution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein. J Mol Biol. 2006 Mar 24;357(2):493-508. PubMed.
- Dahms SO, Hoefgen S, Roeser D, Schlott B, Gührs KH, Than ME. Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5381-6. PubMed.