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J. Biol. Chem., Vol. 279, Issue 48, 50221-50229, November 26, 2004

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Functional Organization of the Sortilin Vps10p Domain^*

Uffe B. Westergaard, Esben S. Sørensen, Guido Hermey, Morten S. Nielsen, Anders Nykjær, Kirstine Kirkegaard, Christian Jacobsen, Jørgen Gliemann, Peder Madsen, and Claus Munck Petersen¶

From the Institute of Medical Biochemistry, Ole Worms Allé, Building 170, and the Protein Chemistry Laboratory, Department of Molecular Biology, Gustav Wieds Vej 10C, University of Aarhus, 8000 Aarhus C, Denmark

A Vps10p domain makes up the entire luminal part of Sortilin, and this type of domain is the hallmark of a new family of neuronal receptors that target a variety of ligands, including neurotrophins and neuropeptides. We have shown that two structural features of the Vps10p domain, the N-terminal propeptide and the C-terminal segment of ten conserved cysteines (10CC), are key elements in the function of Sortilin. The propeptide has two functions. (i) It binds the mature part of Sortilin and prevents ligands in the biosynthetic pathway from binding to the uncleaved proreceptor, and (ii) it facilitates receptor transport in early Golgi compartments by a mechanism that does not depend on its ability to prevent ligand binding. In contrast, other Vps10p domain receptors, such as SorLA and SorCS3, do not need their propeptide for normal and swift processing. The 10CC segment constitutes an exchangeable module containing five conserved disulfide bridges, and using module-shuffling and truncations, we have shown that the 10CC segment is a major ligand-binding region in Sortilin.

Received for publication, August 4, 2004

^* This work is supported by grants from The Danish Medical Research Foundation, The Novo Nordic Foundation, and The Lundbeck 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.

^¶ To whom correspondence should be addressed. Tel.: 45-89422865; Fax: 45-86131160; E-mail: cmp{at}biokemi.au.dk.

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