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The Structural Basis of ZMPSTE24-Dependent Laminopathies

DOI: 10.1126/science.1231513 DOI Help
PMID: 23539603 PMID Help

Authors: A. Quigley (Structural Genomics Consortium, University of Oxford) , Y. Y. Dong (Structural Genomics Consortium, University of Oxford) , A. C. W. Pike (Structural Genomics Consortium, University of Oxford) , L. Dong (Structural Genomics Consortium, University of Oxford) , L. Shrestha (Structural Genomics Consortium, University of Oxford) , G. Berridge (Structural Genomics Consortium, University of Oxford) , P. J. Stansfeld (University of Oxford) , M. S. P. Sansom (University of Oxford) , A. M. Edwards (Structural Genomics Consortium, University of Toronto) , C. Bountra (Structural Genomics Consortium, University of Oxford) , F. Von Delft (Diamond Light Source) , A. N. Bullock (Structural Genomics Consortium, University of Oxford) , N. A. Burgess-brown (Structural Genomics Consortium, University of Oxford) , E. P. Carpenter (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science , VOL 339 (6127) , PAGES 1604 - 1607

State: Published (Approved)
Published: March 2013
Diamond Proposal Number(s): 8421

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 ?-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.

Journal Keywords: Catalytic; Crystallography; X-Ray; Humans; Membrane; Metabolism; Inborn; Metalloendopeptidases; Nuclear; Progeria; Protein; Substrate; Thermolysin

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 02/04/2013 17:26

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