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The "CPC clip motif": a conserved structural signature for heparin-binding proteins.

Torrent M, Nogués MV, Andreu D, Boix E - PLoS ONE (2012)

Bottom Line: However, despite the efforts committed to understand the molecular nature of the interactions in protein-GAG complexes, the answer to this question remains elusive.In the present study the interphases of 20 heparin-binding proteins have been analyzed searching for a conserved structural pattern.The distances between the α carbons and the side chain center of gravity of the residues composing this motif are also conserved.Furthermore, this pattern can be found in other proteins suggested to bind heparin for which no structural information is available.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Biosciences Faculty, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain. marc.torrent@uab.cat

ABSTRACT
Glycosaminoglycans (GAGs) are essential molecules that regulate diverse biological processes including cell adhesion, differentiation, signaling and growth, by interaction with a wide variety of proteins. However, despite the efforts committed to understand the molecular nature of the interactions in protein-GAG complexes, the answer to this question remains elusive.In the present study the interphases of 20 heparin-binding proteins have been analyzed searching for a conserved structural pattern. We have found that a structural motif encompassing one polar and two cationic residues (which has been named the CPC clip motif) is conserved among all the proteins deposited in the PDB. The distances between the α carbons and the side chain center of gravity of the residues composing this motif are also conserved. Furthermore, this pattern can be found in other proteins suggested to bind heparin for which no structural information is available. Hence we propose that the CPC clip motif, working like a staple, is a primary contributor to the attachment of heparin and other sulfated GAGs to heparin-binding proteins.

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Related in: MedlinePlus

Molecular docking simulation of lymphotactin and fractalkine heparin-binding sites.The figure displays the protein electrostatic potential (left) and the protein cartoon highlighting in red the CPC clip motif (right) of lymphotactin Ltn10 (A) and Ltn40 (B) and CDF fractalkine domain (C). CPC residues are colored in blue (cationic) and magenta (polar). Heparin dodecasaccharide ligand used in docking simulations is colored in orange. PDB codes: 1J8I (Ltn10), 2JP1 (Ltn40), 1B2T (fractalkine) and 1HPN (heparin ligand).
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pone-0042692-g004: Molecular docking simulation of lymphotactin and fractalkine heparin-binding sites.The figure displays the protein electrostatic potential (left) and the protein cartoon highlighting in red the CPC clip motif (right) of lymphotactin Ltn10 (A) and Ltn40 (B) and CDF fractalkine domain (C). CPC residues are colored in blue (cationic) and magenta (polar). Heparin dodecasaccharide ligand used in docking simulations is colored in orange. PDB codes: 1J8I (Ltn10), 2JP1 (Ltn40), 1B2T (fractalkine) and 1HPN (heparin ligand).

Mentions: Since a structure for Ltn complexed to heparin or heparin derivatives is unavailable, we have conducted molecular docking simulations (using 1HPN heparin dodesaccharide as a ligand) to find putative heparin binding sites. Our results (Figure 4A,B) suggest that both, the Ltn10 (PDB code 1J8I) and Ltn40 (PDB code 2JP1) can tightly bind heparin (Table 1) through a cationic surface, as described for most chemokines. In this model, Arg and Lys residues provide the main interactions (Arg23, Lys25, Lys42, Arg 43, Lys46, Lys66) and one polar residue (Ser22) is close enough to make hydrogen-bonding contact with the ligand. These results are supported both by NMR and heparin-sepharose chromatography. Particularly, Arg23 and Arg43 are the ones undergoing stronger NMR chemical shifts upon heparin binding [33] and can be viewed as defining a CPC clip motif together with the polar residue Ser22 in both folds (Figure 4A,B), with Cα distances (3.8 Å, 11.7 Å and 8.4 Å for Ltn10 and 3.8 Å, 11.7 Å and 12.0 Å for Ltn40) consistent with reference values.


The "CPC clip motif": a conserved structural signature for heparin-binding proteins.

Torrent M, Nogués MV, Andreu D, Boix E - PLoS ONE (2012)

Molecular docking simulation of lymphotactin and fractalkine heparin-binding sites.The figure displays the protein electrostatic potential (left) and the protein cartoon highlighting in red the CPC clip motif (right) of lymphotactin Ltn10 (A) and Ltn40 (B) and CDF fractalkine domain (C). CPC residues are colored in blue (cationic) and magenta (polar). Heparin dodecasaccharide ligand used in docking simulations is colored in orange. PDB codes: 1J8I (Ltn10), 2JP1 (Ltn40), 1B2T (fractalkine) and 1HPN (heparin ligand).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412806&req=5

pone-0042692-g004: Molecular docking simulation of lymphotactin and fractalkine heparin-binding sites.The figure displays the protein electrostatic potential (left) and the protein cartoon highlighting in red the CPC clip motif (right) of lymphotactin Ltn10 (A) and Ltn40 (B) and CDF fractalkine domain (C). CPC residues are colored in blue (cationic) and magenta (polar). Heparin dodecasaccharide ligand used in docking simulations is colored in orange. PDB codes: 1J8I (Ltn10), 2JP1 (Ltn40), 1B2T (fractalkine) and 1HPN (heparin ligand).
Mentions: Since a structure for Ltn complexed to heparin or heparin derivatives is unavailable, we have conducted molecular docking simulations (using 1HPN heparin dodesaccharide as a ligand) to find putative heparin binding sites. Our results (Figure 4A,B) suggest that both, the Ltn10 (PDB code 1J8I) and Ltn40 (PDB code 2JP1) can tightly bind heparin (Table 1) through a cationic surface, as described for most chemokines. In this model, Arg and Lys residues provide the main interactions (Arg23, Lys25, Lys42, Arg 43, Lys46, Lys66) and one polar residue (Ser22) is close enough to make hydrogen-bonding contact with the ligand. These results are supported both by NMR and heparin-sepharose chromatography. Particularly, Arg23 and Arg43 are the ones undergoing stronger NMR chemical shifts upon heparin binding [33] and can be viewed as defining a CPC clip motif together with the polar residue Ser22 in both folds (Figure 4A,B), with Cα distances (3.8 Å, 11.7 Å and 8.4 Å for Ltn10 and 3.8 Å, 11.7 Å and 12.0 Å for Ltn40) consistent with reference values.

Bottom Line: However, despite the efforts committed to understand the molecular nature of the interactions in protein-GAG complexes, the answer to this question remains elusive.In the present study the interphases of 20 heparin-binding proteins have been analyzed searching for a conserved structural pattern.The distances between the α carbons and the side chain center of gravity of the residues composing this motif are also conserved.Furthermore, this pattern can be found in other proteins suggested to bind heparin for which no structural information is available.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Biosciences Faculty, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain. marc.torrent@uab.cat

ABSTRACT
Glycosaminoglycans (GAGs) are essential molecules that regulate diverse biological processes including cell adhesion, differentiation, signaling and growth, by interaction with a wide variety of proteins. However, despite the efforts committed to understand the molecular nature of the interactions in protein-GAG complexes, the answer to this question remains elusive.In the present study the interphases of 20 heparin-binding proteins have been analyzed searching for a conserved structural pattern. We have found that a structural motif encompassing one polar and two cationic residues (which has been named the CPC clip motif) is conserved among all the proteins deposited in the PDB. The distances between the α carbons and the side chain center of gravity of the residues composing this motif are also conserved. Furthermore, this pattern can be found in other proteins suggested to bind heparin for which no structural information is available. Hence we propose that the CPC clip motif, working like a staple, is a primary contributor to the attachment of heparin and other sulfated GAGs to heparin-binding proteins.

Show MeSH
Related in: MedlinePlus