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.

MT is the recipient of a postdoctoral grant from Alianza Cuatro Universidades (Spain). Work supported by the European Union (HEALTH-F3-2008- 223414), the Spanish Ministry of Science and Innovation (BIO2008-04487-CO3-02, BFU2009- 09371, FEDER funds) and the Generalitat de Catalunya (SGR 2009-494, SGR2009-795