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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 representation of the CPC clip motif for the 20 reference protein-heparin complexes.For each complex, the ligand is colored in orange, the amino acids belonging to the CPC clip motif in green and suggested polar interactions are depicted as blue dashed lines. Images were generated with Pymol.
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pone-0042692-g002: Molecular representation of the CPC clip motif for the 20 reference protein-heparin complexes.For each complex, the ligand is colored in orange, the amino acids belonging to the CPC clip motif in green and suggested polar interactions are depicted as blue dashed lines. Images were generated with Pymol.

Mentions: We have used the PDBePISA server [19] to characterize hydrogen-bonding contacts in the ligand-protein interfaces of the discovery dataset. This analysis shows Arg and Lys residues making the primary hydrogen-bonding contacts. Polar residues, for their part, could fine-tune the precise recognition of GAGs. More specifically, detailed inspection of the interacting residues reveals a conserved pattern that comprises one polar and two positively charged residues (Figure 2) whose spatial arrangement allows defining regular distances between cationic (C and C′) and polar (P) residue α-carbons and side-chain center of gravity (Figure 3). Average measured distances are 6.0±1.8 Å (PC), 11.6±1.6 Å (PC′) and 11.4±2.4 Å (CC′) for Cα and 6.0±1.9 Å (PC), 10.6±1.8 Å (PC′) and 10.7±2.0 Å (CC′) for side-chains center of gravity. Hence our analysis suggests that a structural rather than a sequence pattern appears to be conserved in heparin-binding proteins. Additional contacts involving both side-chain and main-chain atoms can be found in the identified interfaces. These would provide complementary contacts for a fuller fastening of heparin. Thus, the cation-polar-cation (CPC) motif outlined above could be regarded as the minimum structural requirement for heparin binding in proteins. We should also consider that heparin-binding sites could be located in monomers but also in oligomeric interfaces. The CPC motif can thus be shared by two monomers. For example, in structure 1AXM a monomeric and a dimeric binding site can be described where one monomer contains one side of the motif (P and C residues) and the other the remaining residue (C′).


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

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

Molecular representation of the CPC clip motif for the 20 reference protein-heparin complexes.For each complex, the ligand is colored in orange, the amino acids belonging to the CPC clip motif in green and suggested polar interactions are depicted as blue dashed lines. Images were generated with Pymol.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0042692-g002: Molecular representation of the CPC clip motif for the 20 reference protein-heparin complexes.For each complex, the ligand is colored in orange, the amino acids belonging to the CPC clip motif in green and suggested polar interactions are depicted as blue dashed lines. Images were generated with Pymol.
Mentions: We have used the PDBePISA server [19] to characterize hydrogen-bonding contacts in the ligand-protein interfaces of the discovery dataset. This analysis shows Arg and Lys residues making the primary hydrogen-bonding contacts. Polar residues, for their part, could fine-tune the precise recognition of GAGs. More specifically, detailed inspection of the interacting residues reveals a conserved pattern that comprises one polar and two positively charged residues (Figure 2) whose spatial arrangement allows defining regular distances between cationic (C and C′) and polar (P) residue α-carbons and side-chain center of gravity (Figure 3). Average measured distances are 6.0±1.8 Å (PC), 11.6±1.6 Å (PC′) and 11.4±2.4 Å (CC′) for Cα and 6.0±1.9 Å (PC), 10.6±1.8 Å (PC′) and 10.7±2.0 Å (CC′) for side-chains center of gravity. Hence our analysis suggests that a structural rather than a sequence pattern appears to be conserved in heparin-binding proteins. Additional contacts involving both side-chain and main-chain atoms can be found in the identified interfaces. These would provide complementary contacts for a fuller fastening of heparin. Thus, the cation-polar-cation (CPC) motif outlined above could be regarded as the minimum structural requirement for heparin binding in proteins. We should also consider that heparin-binding sites could be located in monomers but also in oligomeric interfaces. The CPC motif can thus be shared by two monomers. For example, in structure 1AXM a monomeric and a dimeric binding site can be described where one monomer contains one side of the motif (P and C residues) and the other the remaining residue (C′).

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