Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex — PNAS

Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex
F. Javier Pérez-Victoriaa,1, Guillermo Abascal-Palaciosb,1, Igor Tascónb, Andrey Kajavac, Javier G. Magadána, Erik P. Piorod, Juan S. Bonifacinoa,2, and Aitor Hierrob,2
+ Author Affiliations

aCell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892;
bStructural Biology Unit, Center for Cooperative Research in Biosciences bioGUNE, Bizkaia Technology Park, 48160 Derio, Spain;
cCentre de Recherches de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique, University of Montpellier, 34293 Montpellier, France; and
dNeuromuscular Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195
Edited by Axel T. Brunger, Stanford University, Stanford, CA, and approved June 15, 2010 (received for review April 7, 2010)

↵1F.J.P.-V. and G.A.-P. contributed equally to this work.

Abstract
The multisubunit Golgi-associated retrograde protein (GARP) complex is required for tethering and fusion of endosome-derived transport vesicles to the trans-Golgi network. Mutation of leucine-967 to glutamine in the Vps54 subunit of GARP is responsible for spinal muscular atrophy in the wobbler mouse, an animal model of amyotrophic lateral sclerosis. The crystal structure at 1.7 Å resolution of the mouse Vps54 C-terminal fragment harboring leucine-967, in conjunction with comparative sequence analysis, reveals that Vps54 has a continuous α-helical bundle organization similar to that of other multisubunit tethering complexes. The structure shows that leucine-967 is buried within the α-helical bundle through predominantly hydrophobic interactions that are critical for domain stability and folding in vitro. Mutation of this residue to glutamine does not prevent integration of Vps54 into the GARP complex but greatly reduces the half-life and levels of the protein in vivo. Severely reduced levels of mutant Vps54 and, consequently, of the whole GARP complex underlie the phenotype of the wobbler mouse.

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Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex — PNAS