title: The structural investigation of glycosaminoglycan binding to CXCL12 displays distinct interaction sites.
abstract: The stromal cell-derived factor 1α (CXCL12) belongs to the CXC chemokine family and plays an important role in tissue regeneration and the recruitment of stem cells. Here, a stable chemotactic gradient is essential that is formed by the interaction of CXCL12 with the extracellular matrix. Binding properties of CXCL12 to naturally occurring glycosaminoglycans (GAGs) as well as to the artificial highly sulfated hyaluronic acid (HA) are investigated by using a combination of NMR spectroscopy, molecular modeling and molecular dynamics simulations. Our results demonstrate a preferred protein binding for the sulfated GAGs heparin (HE) and highly sulfated HA. Furthermore, we could demonstrate that the orientation of the sulfate is crucial for binding. All sulfated GAGs interact with the CXCL12 GAG-binding motif (K24-H25-L26-K27-R41-K43-R47), where K27 and R41 represent the anchor points. Furthermore, differences could be observed in the second interaction interface of CXCL12: both HE and highly sulfated HA interfere with the receptor-binding motif, while chondroitin sulfate binds different amino acids in close proximity to this motif. CXCL12 does not interact with HA, which was directly demonstrated by NMR spectroscopy and molecular modeling and explained by the lack of sulfate groups of the HA molecule.
authors: Institute of Biochemistry, Universität Leipzig, Leipzig 04103, Germany.
authors: Nydia
authors: N
authors: Panitz
authors: Institute for Medical Physics and Biophysics, Universität Leipzig, Leipzig 04107, Germany.
authors: Stephan
authors: S
authors: Theisgen
authors: BIOTEC, Technische Universität Dresden, Dresden 01307, Germany.
authors: Sergey A
authors: SA
authors: Samsonov
authors: BIOTEC, Technische Universität Dresden, Dresden 01307, Germany.
authors: Jan-Philip
authors: JP
authors: Gehrcke
authors: Institute of Biochemistry, Universität Leipzig, Leipzig 04103, Germany.
authors: Lars
authors: L
authors: Baumann
authors: Institute of Biochemistry, Universität Leipzig, Leipzig 04103, Germany.
authors: Kathrin
authors: K
authors: Bellmann-Sickert
authors: Institute for Medical Physics and Biophysics, Universität Leipzig, Leipzig 04107, Germany.|Institute of Pharmacy, Freie Universität Berlin, Berlin 14195, Germany.
authors: Sebastian
authors: S
authors: Köhling
authors: BIOTEC, Technische Universität Dresden, Dresden 01307, Germany.
authors: M Teresa
authors: MT
authors: Pisabarro
authors: Institute for Medical Physics and Biophysics, Universität Leipzig, Leipzig 04107, Germany.|Institute of Pharmacy, Freie Universität Berlin, Berlin 14195, Germany.
authors: Jörg
authors: J
authors: Rademann
authors: Institute for Medical Physics and Biophysics, Universität Leipzig, Leipzig 04107, Germany.
authors: Daniel
authors: D
authors: Huster
authors: Institute of Biochemistry, Universität Leipzig, Leipzig 04103, Germany abeck-sickinger@uni-leipzig.de.
authors: Annette G
authors: AG
authors: Beck-Sickinger
mesh_terms: D001665:Binding Sites; D002236:Carbohydrate Conformation; D054377:Chemokine CXCL12 / Q000737:chemistry*; D006025:Glycosaminoglycans / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D006025:Glycosaminoglycans
keywords: CXCL12; HSQC NMR; glycosaminoglycans; molecular modeling