Functional organization of the sortilin Vps10p domain.
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.
Westergaard
Uffe B
UB
Institute of Medical Biochemistry, Ole Worms Allé, Building 170, University of Aarhus, Aarhus, Denmark.
Sørensen
Esben S
ES
Hermey
Guido
G
Nielsen
Morten S
MS
Nykjaer
Anders
A
Kirkegaard
Kirstine
K
Jacobsen
Christian
C
Gliemann
Jørgen
J
Madsen
Peder
P
Petersen
Claus Munck
CM
D033942:Adaptor Proteins, Vesicular Transport; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D020349:Surface Plasmon Resonance; D013997:Time Factors; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D004220:Disulfides; D008024:Ligands; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D000099183:Sortilin