Download MendeleyThe Structural Basis of Zmpste24-Dependent Laminopathies.
Quigley, A., Dong, Y.Y., Pike, A.C.W., Dong, L., Shrestha, L., Berridge, G., Stansfeld, P.J., Sansom, M.S.P., Edwards, A.M., Bountra, C., von Delft, F., Bullock, A.N., Burgess-Brown, N.A., Carpenter, E.P.(2013) Science 339: 1604
- PubMed: 23539603
- DOI: https://doi.org/10.1126/science.1231513
- Primary Citation of Related Structures:
2YPT, 4AW6 - PubMed Abstract:
Mutations in the nuclear membrane zinc metalloprotease ZMPSTE24 lead to diseases of lamin processing (laminopathies), such as the premature aging disease progeria and metabolic disorders. ZMPSTE24 processes prelamin A, a component of the nuclear lamina intermediate filaments, by cleaving it at two sites. Failure of this processing results in accumulation of farnesylated, membrane-associated prelamin A. The 3.4 angstrom crystal structure of human ZMPSTE24 has a seven transmembrane α-helical barrel structure, surrounding a large, water-filled, intramembrane chamber, capped by a zinc metalloprotease domain with the catalytic site facing into the chamber. The 3.8 angstrom structure of a complex with a CSIM tetrapeptide showed that the mode of binding of the substrate resembles that of an insect metalloprotease inhibitor in thermolysin. Laminopathy-associated mutations predicted to reduce ZMPSTE24 activity map to the zinc metalloprotease peptide-binding site and to the bottom of the chamber.
Organizational Affiliation:
Structural Genomics Consortium, University of Oxford, Oxford, UK.
