title: The structural basis of ZMPSTE24-dependent laminopathies.
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.
authors.affiliation: Structural Genomics Consortium, University of Oxford, Oxford, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Quigley
authors.forename: Yin Yao
authors.initials: YY
authors.lastname: Dong
authors.forename: Ashley C W
authors.initials: AC
authors.lastname: Pike
authors.forename: Liang
authors.initials: L
authors.lastname: Dong
authors.forename: Leela
authors.initials: L
authors.lastname: Shrestha
authors.forename: Georgina
authors.initials: G
authors.lastname: Berridge
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stansfeld
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
authors.forename: Aled M
authors.initials: AM
authors.lastname: Edwards
authors.forename: Chas
authors.initials: C
authors.lastname: Bountra
authors.forename: Frank
authors.initials: F
authors.lastname: von Delft
authors.forename: Alex N
authors.initials: AN
authors.lastname: Bullock
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Burgess-Brown
authors.forename: Elisabeth P
authors.initials: EP
authors.lastname: Carpenter
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D034904:Lamin Type A; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D008661:Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000235:genetics; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011371:Progeria / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D011498:Protein Precursors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D013820:Thermolysin / Q000737:chemistry
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; C090764:prelamin A; D008666:Metalloendopeptidases; D013820:Thermolysin; C120130:ZMPSTE24 protein, human