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J. Biol. Chem., Vol. 280, Issue 50, 41576-41583, December 16, 2005

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The Two Thrombospondin Type I Repeat Domains of the Heparin-binding Growth-associated Molecule Bind to Heparin/Heparan Sulfate and Regulate Neurite Extension and Plasticity in Hippocampal Neurons^*

Erkki Raulo1, Sarka Tumova, Ivan Pavlov, Mari Pekkanen, Anni Hienola, Emilia Klankki, Nisse Kalkkinen, Tomi Taira, Ilkka Kilpelaïnen¶, and Heikki Rauvala2

From the ^¶Department of Chemistry, Neuroscience Center, and Institute of Biotechnology, University of Helsinki, Helsinki FIN-00014, Finland

HB-GAM (heparin-binding growth-associated molecule, also designated as pleiotrophin) and midkine form a two-member family of extracellular matrix proteins that bind tightly to sulfated carbohydrate structures such as heparan sulfate. These proteins are used by developing neurons as extracellular cues in axonal growth and guidance. HB-GAM was recently reported to enhance differentiation of neural stem cells. Based on the solution structure of HB-GAM, we have recently shown that HB-GAM consists of two -sheet domains flanked by flexible lysine-rich N- and C-terminal tails with no apparent structure. These domains are homologous to thrombospondin type I repeats present in numerous extracellular proteins that interact with the cell surface. Our findings showed that the two -sheet domains fold independently. We showed that the domains (but not the lysine-rich tails) in HB-GAM are required and sufficient for interaction with hippocampal neurons. The individual domains bind heparan sulfate weakly and fail to produce significant biological effects in neurite outgrowth and long term potentiation assays. The amino acids in the linker region joining the two domains may be replaced with glycines with no effect on protein function. These results suggest a co-operative action of the two -sheet domains in the biologically relevant interaction with neuron surface heparan sulfate.

Received for publication, June 14, 2005 , and in revised form, September 6, 2005.

^* This work was supported by the Academy of Finland and the Technical Research Centre of Finland (Programme of Molecular Neurobiology), and the Sigrid Jusélius Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Neuroscience Center, University of Helsinki, Viikinkaari 4, P. O. Box 56, Fin-00014, Finland. E-mail: erkki.raulo{at}helsinki.fi.

² To whom correspondence may be addressed: Neuroscience Center, University of Helsinki, Viikinkaari 4, P. O. Box 56, Fin-00014, Finland. E-mail: heikki.rauvala{at}helsinki.fi.

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