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Interaction of the amyloid precursor protein-like protein 1 (APLP1) E2 domain with heparan sulfate involves two distinct binding modes.

Dahms SO, Mayer MC, Roeser D, Multhaup G, Than ME - Acta Crystallogr. D Biol. Crystallogr. (2015)

Bottom Line: APP and its paralogues APP-like protein 1 (APLP1) and APP-like protein 2 (APLP2) contain the highly conserved heparan sulfate (HS) binding domain E2, which effects various (patho)physiological functions.Terminal binding of APLP1 E2 to heparin specifically involves a structure of the nonreducing end that is very similar to heparanase-processed HS chains.These data reveal a conserved mechanism for the binding of APP-family proteins to HS and imply a specific regulatory role of HS modifications in the biology of APP and APP-like proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Protein Crystallography Group, Leibniz Institute for Age Research (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.

ABSTRACT
Beyond the pathology of Alzheimer's disease, the members of the amyloid precursor protein (APP) family are essential for neuronal development and cell homeostasis in mammals. APP and its paralogues APP-like protein 1 (APLP1) and APP-like protein 2 (APLP2) contain the highly conserved heparan sulfate (HS) binding domain E2, which effects various (patho)physiological functions. Here, two crystal structures of the E2 domain of APLP1 are presented in the apo form and in complex with a heparin dodecasaccharide at 2.5 Å resolution. The apo structure of APLP1 E2 revealed an unfolded and hence flexible N-terminal helix αA. The (APLP1 E2)2-(heparin)2 complex structure revealed two distinct binding modes, with APLP1 E2 explicitly recognizing the heparin terminus but also interacting with a continuous heparin chain. The latter only requires a certain register of the sugar moieties that fits to a positively charged surface patch and contributes to the general heparin-binding capability of APP-family proteins. Terminal binding of APLP1 E2 to heparin specifically involves a structure of the nonreducing end that is very similar to heparanase-processed HS chains. These data reveal a conserved mechanism for the binding of APP-family proteins to HS and imply a specific regulatory role of HS modifications in the biology of APP and APP-like proteins.

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Different heparin-binding modes of APLP1 E2. The interactions of APLP1 E2 and the bound heparin chains are shown as schematic diagrams. Amino-acid side chains of individual protein chains are coloured magenta (chain a) or cyan (chain b). Heparin is coloured grey. Interactions between amino-acid side chains and sugar residues are highlighted by orange dashes with interaction distances indicated in Å. (a) Interactions of heparin chain a with APLP1 E2. (b) Interactions of heparin chain b with APLP1 E2. The interaction map was prepared with LIGPLOT (Wallace et al., 1995 ▶).
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fig4: Different heparin-binding modes of APLP1 E2. The interactions of APLP1 E2 and the bound heparin chains are shown as schematic diagrams. Amino-acid side chains of individual protein chains are coloured magenta (chain a) or cyan (chain b). Heparin is coloured grey. Interactions between amino-acid side chains and sugar residues are highlighted by orange dashes with interaction distances indicated in Å. (a) Interactions of heparin chain a with APLP1 E2. (b) Interactions of heparin chain b with APLP1 E2. The interaction map was prepared with LIGPLOT (Wallace et al., 1995 ▶).

Mentions: The terminal Δ4UAp2S-GlcNpS6S disaccharide unit of heparin chain a is bound by the amino-acid side chains of Lys314, Arg369 and His433 of each protomer of the antiparallel APLP1 E2 assembly (Figs. 3 ▶a and 4 ▶a), albeit in different geometries. A total of four charged hydrogen bonds are formed to Δ44UAp2S 1a, involving its carboxyl and 2-O-sulfo moieties. The interactions of APLP1 E2 with GlcNpS6S 2a involve its 2-N-sulfo and 6-O-sulfo groups.


Interaction of the amyloid precursor protein-like protein 1 (APLP1) E2 domain with heparan sulfate involves two distinct binding modes.

Dahms SO, Mayer MC, Roeser D, Multhaup G, Than ME - Acta Crystallogr. D Biol. Crystallogr. (2015)

Different heparin-binding modes of APLP1 E2. The interactions of APLP1 E2 and the bound heparin chains are shown as schematic diagrams. Amino-acid side chains of individual protein chains are coloured magenta (chain a) or cyan (chain b). Heparin is coloured grey. Interactions between amino-acid side chains and sugar residues are highlighted by orange dashes with interaction distances indicated in Å. (a) Interactions of heparin chain a with APLP1 E2. (b) Interactions of heparin chain b with APLP1 E2. The interaction map was prepared with LIGPLOT (Wallace et al., 1995 ▶).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356362&req=5

fig4: Different heparin-binding modes of APLP1 E2. The interactions of APLP1 E2 and the bound heparin chains are shown as schematic diagrams. Amino-acid side chains of individual protein chains are coloured magenta (chain a) or cyan (chain b). Heparin is coloured grey. Interactions between amino-acid side chains and sugar residues are highlighted by orange dashes with interaction distances indicated in Å. (a) Interactions of heparin chain a with APLP1 E2. (b) Interactions of heparin chain b with APLP1 E2. The interaction map was prepared with LIGPLOT (Wallace et al., 1995 ▶).
Mentions: The terminal Δ4UAp2S-GlcNpS6S disaccharide unit of heparin chain a is bound by the amino-acid side chains of Lys314, Arg369 and His433 of each protomer of the antiparallel APLP1 E2 assembly (Figs. 3 ▶a and 4 ▶a), albeit in different geometries. A total of four charged hydrogen bonds are formed to Δ44UAp2S 1a, involving its carboxyl and 2-O-sulfo moieties. The interactions of APLP1 E2 with GlcNpS6S 2a involve its 2-N-sulfo and 6-O-sulfo groups.

Bottom Line: APP and its paralogues APP-like protein 1 (APLP1) and APP-like protein 2 (APLP2) contain the highly conserved heparan sulfate (HS) binding domain E2, which effects various (patho)physiological functions.Terminal binding of APLP1 E2 to heparin specifically involves a structure of the nonreducing end that is very similar to heparanase-processed HS chains.These data reveal a conserved mechanism for the binding of APP-family proteins to HS and imply a specific regulatory role of HS modifications in the biology of APP and APP-like proteins.

View Article: PubMed Central - HTML - PubMed

Affiliation: Protein Crystallography Group, Leibniz Institute for Age Research (FLI), Beutenbergstrasse 11, 07745 Jena, Germany.

ABSTRACT
Beyond the pathology of Alzheimer's disease, the members of the amyloid precursor protein (APP) family are essential for neuronal development and cell homeostasis in mammals. APP and its paralogues APP-like protein 1 (APLP1) and APP-like protein 2 (APLP2) contain the highly conserved heparan sulfate (HS) binding domain E2, which effects various (patho)physiological functions. Here, two crystal structures of the E2 domain of APLP1 are presented in the apo form and in complex with a heparin dodecasaccharide at 2.5 Å resolution. The apo structure of APLP1 E2 revealed an unfolded and hence flexible N-terminal helix αA. The (APLP1 E2)2-(heparin)2 complex structure revealed two distinct binding modes, with APLP1 E2 explicitly recognizing the heparin terminus but also interacting with a continuous heparin chain. The latter only requires a certain register of the sugar moieties that fits to a positively charged surface patch and contributes to the general heparin-binding capability of APP-family proteins. Terminal binding of APLP1 E2 to heparin specifically involves a structure of the nonreducing end that is very similar to heparanase-processed HS chains. These data reveal a conserved mechanism for the binding of APP-family proteins to HS and imply a specific regulatory role of HS modifications in the biology of APP and APP-like proteins.

Show MeSH
Related in: MedlinePlus