Structure and function of ZMPSTE24, an integral membrane protease mutated in progeria

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One of the most serious global challenges over the next 30 years will be to address the profound implications of ageing for global economies and society. A recent UN report predicted that by 2050, 22% of the world's population will be over age 60. Maintaining physical and mental health requires increasing intervention with age, with most people requiring at least three forms of routine treatment in their 80s. There is therefore a pressing need to understand the mechanisms for ageing-related diseases, such as stroke and coronary heart disease.Premature ageing syndromes such as Hutchinson-Gilford progeria syndrome (HGPS) can help us to understand the causes of normal ageing. Children with HGPS manifest many of the features observed in physiologic ageing, including balding, thinning skin and artherosclerosis. They usually die in their teens from a stroke or heart disease. HGPS is caused by a defect in one the components of the structural scaffolding for the cell nucleus, which acts as an anchor point for nuclear proteins and DNA. When this scaffold is disrupted, the cell nucleus is misshapen; chromosomes are disorganised; and cells are unable to divide effectively. These features have been observed in cells from normal 80-year-olds, particularly in the vascular wall, where artherosclerosis takes place. This problem occurs because one of the proteins that forms part of the scaffold, prelamin A, is not correctly processed. In particular, the mutant prelamin A is not processed correctly by an enzyme called ZMPSTE24.We recently succeeded in producing active ZMPSTE24 enzyme and went on to solve its three-dimensional structure using X-ray crystallography (Quigley et al., Science, 2013). This exciting development gives us, for the first time, a framework to understand some of the biochemical mechanisms leading to premature ageing. The structure looked like nothing ever seen before. ZMPSTE24 forms a barrel surrounding a huge water-filled chamber inside the nuclear membrane, with its enzymatic domain at one end. There are a series of side portals in the chamber wall that permit access to inside the barrel. We now plan to define how ZMPSTE24 cleaves its substrates and why mutations in ZMPSTE24 cause disease. By understanding these underlying biochemical mechanisms, we better understand diseases of ageingageing, and possibly even develop treatments for the children who suffer from premature ageing.