Heparin-Binding Growth-Associated Molecule Contains Two Heparin Binding b-Sheet Domains That Are Homologous to the Thrombospondin Type I Repeat

Kilpeläinen, I.
Kaksonen, M.
Kinnunen, T.
Avikainen, H.
Linhardt, Robert J.
Fath, M.
Raulo, E.
Rauvala, H.
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Heparin-Binding Growth-Associated Molecule Contains Two Heparin Binding b-Sheet Domains That Are Homologous to the Thrombospondin Type I Repeat I. Kilpeläinen, M. Kaksonen, T. Kinnunen, H. Avikainen, R.J. Linhardt, M. Fath, E. Raulo, H. Rauvala, Journal of Biological Chemistry, 275, 13564-13570, 2000.
Heparin-binding growth-associated molecule (HB-GAM) is an extracellular matrix-associated protein implicated in the development and plasticity of neuronal connections of brain. Binding to cell surface heparan sulfate is indispensable for the biological activity of HB-GAM. In the present paper we have studied the structure of recombinant HB-GAM using heteronuclear NMR. These studies show that HB-GAM contains two β-sheet domains connected by a flexible linker. Both of these domains contain three antiparallel β-strands. In addition to this domain structure, HB-GAM contains the N- and C-terminal lysine-rich sequences that lack a detectable structure and appear to form random coils. Studies using CD and NMR spectroscopy suggest that HB-GAM undergoes a conformational change upon binding to heparin, and that the binding occurs primarily to the β-sheet domains of the protein. Search of sequence data bases shows that the β-sheet domains of HB-GAM are homologous to the thrombospondin type I repeat (TSR). Sequence comparisions show that the β-sheet structures found previously in midkine, a protein homologous with HB-GAM, also correspond to the TSR motif. We suggest that the TSR sequence motif found in various extracellular proteins defines a β-sheet structure similar to that found in HB-GAM and midkine. In addition to the apparent structural similarity, a similarity in biological functions is suggested by the occurrence of the TSR sequence motif in a wide variety of proteins that mediate cell-to-extracellular matrix and cell-to-cell interactions, in which the TSR domain mediates specific cell surface binding.
Journal of Biological Chemistry, 275, 13564-13570
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