ZMPSTE24 and Premature Ageing: A Unique Integral Membrane Metalloprotease with a Hole in the Middle

Abstract

The nuclear lamina is an intermediate filament network which underlies the nuclear membrane, providing rigidity for the nucleus and a binding site for chromatin and nuclear proteins.The lamina are important in a range of processes including cell division, DNA repair and epigenetic effects. These filaments are made up of three proteins, lamins A, B and C, two of which, lamins A and B, undergo a series of post translational modifications. Failure of lamin processing leads to a series of laminopathies including the premature ageing syndrome Hutchinson Gilford progeria syndrome and mandibuloacral dysplasia. Mature lamin A is formed from its precursor, prelamin A, by farnesylation on a C-terminal CaaX motif, removal of the aaX residues and C-terminal carboxymethylation. Finally prelamin A also undergoes a proteolytic removal of the C-terminal 15 residues, including the farnesylated Cysteine. ZMPSTE24, a nuclear membrane zinc metalloprotease, can perform both the proteolysis steps in this process. Although the first reaction can be performed by RCE1 as well, the second cleavage is only performed by ZMPSTE24.Our crystal structure of ZMPSTE24 revealed a completely unexpected fold, with a seven transmembrane α helical barrel, surrounding a huge, intramembrane chamber (Quigley et al., Science, 339, 1604-7, 2013). One end of the chamber is capped by a zinc metalloprotease. fold, with the active site pointing into the chamber. The C-terminal farnesylated tail of prelamin A will enter into the chamber from the membrane/ nucleoplasm interface, undergo the first processing, be carboxymethylated by ICMT and then reinsert into the ZMPSTE24 chamber to have the final 15 residues, including the farnesylated cysteine, removed. Some laminopathies are caused by point mutations on ZMPSTE24 and our structure has allowed us to understand how these mutations affect the function of ZMPSTE24.