3n1e | pdb_00003n1e
Vps54 C-terminal domain
Structural highlights
Disease[VPS54_MOUSE] Note=Defects in Vps54 are the cause of wobbler phenotype (wr). Wr is autosomal recessive and is a spontaneous mutation discovered almost 50 years ago. It causes spinal muscular atrophy and defective spermiogenesis.[1] Function[VPS54_MOUSE] May be involved in retrograde transport from early and late endosomes to the late Golgi. The GARP complex is required for the maintenance of the cycling of mannose 6-phosphate receptors between the TGN and endosomes, this cycling is necessary for proper lysosomal sorting of acid hydrolases such as CTSD (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe 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 A resolution of the mouse Vps54 C-terminal fragment harboring leucine-967, in conjunction with comparative sequence analysis, reveals that Vps54 has a continuous alpha-helical bundle organization similar to that of other multisubunit tethering complexes. The structure shows that leucine-967 is buried within the alpha-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. Structural basis for the wobbler mouse neurodegenerative disorder caused by mutation in the Vps54 subunit of the GARP complex.,Perez-Victoria FJ, Abascal-Palacios G, Tascon I, Kajava A, Magadan JG, Pioro EP, Bonifacino JS, Hierro A Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):12860-5. Epub 2010 Jul 6. PMID:20615984[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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