Chime Tutorial of the 3D Structure of Human APP N-Terminal Heparin Binding Domain

CPK Color Scheme

The following is an interactive tour of Human Amyloid Precursor Protein (APP) N-terminal Heparin binding domain. Click on the buttons below in the order presented to learn how structure of this domain relates to its proposed function as a growth factor. In order to view the chime image of APP in the left frame of this page, be sure to download and activate the Chime plugin from the MDL website.

Human Amyloid Precursor Protein is a transmembrane, multi-domain, multi-isoform protein. The 695 amino acid isoform is expressed primarily in brain tissue and has been linked to Alzheimer's disease. The N-terminal Heparin binding domain is a short region of the extracellular portion of APP. It consists of amino acid residues 28-123 and was first crystallized by Rossjohn J, et al. to 1.8 Å (1999). The N-terminal Heparin binding domain plays a significant role in neurite outgrowth (Small DH, et al., 1994) and possesses similarities to cysteine-rich growth factors. For a more complete review of APP, please visit Jackie's first and second assignments.


To reset the view of Amyloid Precursor Protein N-Terminal domain and begin the tutorial, click here.


Secondary Structure

The N-terminal heparin binding domain of APP consists of nine ß-sheets. To visualize these ß-sheets as blue ribbons, click here.

These ß-sheets are very short, containing three to five amino acids each. To visualize each amino acid by color, click here.

The N-terminal heparin binding domain also has one alpha helix as part of its secondary structure. Thirteen amino acids make up this helix, which represents the longest portion of secondary structure (Rossjohn J, et al., 1999). The helix will appear as a cartoon colored by individual amino acids when you click here.

Click here to see the alpha helix and -sheets colored by amino acids together as the domain rotates.


Tertiary Structure

Note that the N-terminal heparin binding domain of APP contains several cysteine amino acids. The yellow portions of the secondary structure ribbons/cartoons represent cysteines. Click here to see the six cysteines (C38, C62, C73, C98, C105, C117) highlighted in yellow spacefill and labeled in black. Interestingly, these cysteines have been strictly conserved amongst the APP orthologs, which suggests that they are functionally significant (Rossjohn J, et al., 1999).

These six cysteines form three pairs with disulfide bonds between them. Disulfide bonds hold the peptide chain together in the correct 3D shape and are located where the spacefill cysteines are touching. The third disulfide bond, between C98 and C105, is particularly important. To visualize this disulfide bonds as a dashed line, click here. N.B. The view remains the same as the previous image, but other parts of the domain are hidden for emphasis.

To show the rest of the domain again, click here.


Heparin Binding Site

The disulfide bond between cysteine residues 98 and 105 tethers the peptide chain such that several positively charged amino acids are in the same area. These residues (R 40, K 60, K 99, R 100, R 102, K 103, K 106, H 108, and H 110) form a basic surface on one side of the APP N-terminal domain. This postive surface can be seen in spacefill blue by clicking here. The ribbons disappear for clarity.

The basic, positively charged surface on the N-terminal domain of APP attracts the acidic, negatively charged glycoaminoglycan, heparin. Scientists have specifically identified residues 96-110 as the heparin binding site (Small DH, et al., 1994). Click here to highlight the heparin binding site in orange.

While the not all of positive surface (blue) comprises the heparin binding site (orange), it accounts a large portion of the site. Furthermore, though there does not appear to be a definite 'groove' for a heparin molecule per se, the C98-C105 disulfide bond makes the N-terminal flexible. Rossjohn J, et al. have suggested an induced fit model of binding (1999). Heparin binding is associated with the stimulation of neuronal outgrowth, which is appears to be the N-terminal domain's main function.

Indeed, because N-terminal domain of APP contains many cysteines and regulates neuronal outgrowth via the heparin binding site, scientists classify it as cysteine-rich growth factor-like. Further investigation must be conducted to determine if the N-terminal domain of APP is, in fact, a growth factor.

Click here to reset the N-terminal Heparin binding domain.


Kogoy J, Campbell AM. March 2005. Manual for Making A Chime Tutorial. Accessed 2005 Apr 4.

Rossjohn J, et al. 1999 Apr. Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Nature Structural Biology 6 (4): 327-331.

Small DH, et al. 1994 Apr. A Heparin-binding Domain in the Amyloid Protein Precursor of Alzheimer's Disease is Involved in the Regulation of Neurite Outgrowth. The Journal of Neuroscience 14 (4): 2117-2127.