2YPT

Crystal structure of the human nuclear membrane zinc metalloprotease ZMPSTE24 mutant (E336A) in complex with a synthetic CSIM tetrapeptide from the C-terminus of prelamin A

Summary for 2YPT

• Entry DOI: 10.2210/pdb2ypt/pdb
• Descriptor: CAAX PRENYL PROTEASE 1 HOMOLOG, PRELAMIN-A/C, ZINC ION (3 entities in total)
• Functional Keywords: hydrolase-peptide complex, m48 peptidase, integral membrane protein, prelamin a processing, ageing, progeria, hydrolase/peptide
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Endoplasmic reticulum membrane ; Multi-pass membrane protein : O75844; Nucleus. Isoform C: Nucleus speckle : P02545
• Total number of polymer chains: 8
• Total formula weight: 224665.88

Authors

Pike, A.C.W.,Dong, Y.Y.,Quigley, A.,Dong, L.,Savitsky, P.,Cooper, C.D.O.,Chaikuad, A.,Goubin, S.,Shrestha, L.,Li, Q.,Mukhopadhyay, S.,Yang, J.,Xia, X.,Shintre, C.A.,Barr, A.J.,Berridge, G.,Chalk, R.,Bray, J.E.,von Delft, F.,Bullock, A.,Bountra, C.,Arrowsmith, C.H.,Edwards, A.,Burgess-Brown, N.,Carpenter, E.P. (deposition date: 2012-11-01, release date: 2012-12-05, Last modification date: 2024-05-08)

Primary citation

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.
The Structural Basis of Zmpste24-Dependent Laminopathies.
Science, 339:1604-, 2013

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.

PubMed: 23539603
DOI: 10.1126/SCIENCE.1231513

Experimental method

X-RAY DIFFRACTION (3.8 Å)