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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.

Original publication

DOI

10.1126/science.1231513

Type

Journal article

Journal

Science

Publication Date

29/03/2013

Volume

339

Pages

1604 - 1607

Keywords

Amino Acid Sequence, Catalytic Domain, Crystallography, X-Ray, Humans, Lamin Type A, Membrane Proteins, Metabolism, Inborn Errors, Metalloendopeptidases, Molecular Sequence Data, Nuclear Proteins, Progeria, Protein Conformation, Protein Precursors, Substrate Specificity, Thermolysin