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Functional organization of the sortilin Vps10p domain.

Research paper by Uffe B UB Westergaard, Esben S ES Sørensen, Guido G Hermey, Morten S MS Nielsen, Anders A Nykjaer, Kirstine K Kirkegaard, Christian C Jacobsen, Jørgen J Gliemann, Peder P Madsen, Claus Munck CM Petersen

Indexed on: 15 Sep '04Published on: 15 Sep '04Published in: Journal of Biological Chemistry



Abstract

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.