Distant homologies and domain conservation of the Hereditary Spastic Paraplegia protein SPG11/ALS5/spatacsin

Loss-of-function mutations in SPG11 protein (spatacsin) are a common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. To identify regions of the protein that may have functions that are disrupted in disease, we carried out bioinformatic analyses of its conserved regions. An N-terminal region of around 650 amino-acid residues, present in SPG11 across a wide range of metazoan animals, was missing from many insect lineages. Evolutionary loss of this domain correlated with loss of its binding partner, the AP-5 adaptor complex, suggesting that its main function is interaction with AP-5 in intracellular trafficking, and that the remainder of SPG11 carries out AP-5-independent functions. At the C-terminus of SPG11, a spatacsin_C domain showed sequence similarity and predicted structural homology to the Vps16_C domain of the HOPS complex protein Vps16. It localized partly to acidic compartments, consistent with a role in endolysosomal or autolysosomal transport, like Vps16. Mass spectrometry analysis of binding partners of this domain identified actin cytoskeletal and proteasome proteins, some SM proteins, and a number of aminoacyl-tRNA synthetases. Since mutations affecting SPG11 or aminoacyl-tRNA synthetases can cause Charcot-Marie-Tooth neuropathy (CMT), we suggest autolysosomal trafficking, and in particular autophagic lysosome reformation, as a target process in CMT.