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Human Paraplegin, AAA domain in complex with ADP

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PDB Code 2QZ4 Target Class ATPases Target SPG7 Alias CAR, CMAR, FLJ37308, MGC126331, MGC126332, PGN, SPG5C, SPG7 Disease Area/Function neurobiology Date Deposited Aug 16 2007 Authors T.KARLBERG, L.LEHTIO, C.H.ARROWSMITH, H.BERGLUND, R.D.BUSAM, R.COLLINS, L.G.DAHLGREN, A.EDWARDS, S.FLODIN, A.FLORES, S.GRASLUND, M.HAMMARSTROM, M.D.HERMAN, I.JOHANSSON, A.KALLAS, T.KOTENYOVA, M.MOCHE, M.E.NILSSON, P.NORDLUND, T.NYMAN, C.PERSSON, J.SAGEMARK, M.SUNDSTROM, L.SVENSSON, A.G.THORSELL, L.TRESAUGES, S.VAN DEN BERG, J.WEIGELT, M.WELIN, L.HOLMBERG-SCHIAVONE

About this structure

Human Paraplegin (SPG7) is an ATP-dependent m-AAA protease in mitochondria and is specifically shown to be involved in ribosome maturation. Mutations in the spg7 gene cause axonal degeneration in hereditary spastic paraplegia (HSP). The disease is most commonly manifested in spasticity and weakness of the lower limbs.

Paraplegin belongs to the AAA+ superfamily (ATPases associated with a variety of cellular activities) and consists of three identifiable domains: an extracellular FtsH-domain which is found in membrane-bound ATP-dependent proteases, an AAA-domain and a peptidase M41 domain, which is a metalloprotease domain. The protein is located to the inner mitochondrial membrane.

Here, the crystal structure of the AAA-domain of human Paraplegin is presented in complex with the nucleotide ADP at 2.2 Å resolution. The overall structure is comprised of a five-stranded parallel β–sheet flanked by α–helices, that together with a four-helix bundle is forming the nucleotide binding pocket. The nucleotide ADP was clearly seen in the electron density, however no magnesium was observed despite high concentrations in purification and crystallization conditions. The β–phosphate of ADP was seen bound to a conserved P-loop motif (GPPGCGKT). In bacteria a conserved orthologue, the ATP-dependent metalloprotease FtsH has been structurally determined (the AAA-domain and the protease domain). The overall architecture is that of a hexamer. The presented structure of the AAA-domain of human Paraplegin alone is however monomeric.

References

  1. Casari G., De-Fusco M., Ciarmatori S., Zeviani M., Mora M., Fernandez P., DeMichele G., Filla A., Cocozza S., Marconi R., Durr A., Fontaine B. and Ballabio A. (1998). Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 93, 973–983.
  2. Rugarli E.I. and Langer T. (2006). Translation m-AAA protease function in mitochondria to hereditary spastic paraplegia. Trends Mol. Med. 12, 262-269.
  3. 3. Bieniossek C., Schalch T., Bumann M., Meister M., Meier R. and Baumann U. (2006). The molecular architecture of the metalloprotease FtsH. Proc. Nat. Acad. Sci. 103, 3066-3071.