ZMPSTE24, an integral membrane zinc metalloprotease with a connection to progeroid disorders

Department of Cell Biology, The Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
Biological Chemistry (Impact Factor: 3.27). 06/2009; 390(8):761-73. DOI: 10.1515/BC.2009.080
Source: PubMed


ZMPSTE24 is an integral membrane zinc metalloprotease originally discovered in yeast as an enzyme (called Ste24p) required for maturation of the mating pheromone a-factor. Surprisingly, ZMPSTE24 has recently emerged as a key protease involved in human progeroid disorders. ZMPSTE24 has only one identified mammalian substrate, the precursor of the nuclear scaffold protein lamin A. ZMPSTE24 performs a critical endoproteolytic cleavage step that removes the hydrophobic farnesyl-modified tail of prelamin A. Failure to do so has drastic consequences for human health and longevity. Here, we discuss the discovery of the yeast and mammalian ZMPSTE24 orthologs and review the unexpected connection between ZMPSTE24 and premature aging.

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    • "An additional processing step distinguishes prelamin A from lamin B and other CAAX proteins. This step is cleavage of the final 15 residues, including the post-translationally modified C-terminal tail, and is mediated by the zinc metalloprotease ZMPSTE24 to yield unmodified mature lamin A [Barrowman and Michaelis, 2009; Davies et al., 2009]. "
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    ABSTRACT: Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2013; 161(7). DOI:10.1002/ajmg.a.35971 · 2.16 Impact Factor
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    • "Children with HGPS generally do not survive past adolescence, usually succumbing to a geriatric disease such as atherosclerosis (Pollex and Hegele 2004). The enzyme in humans believed to be responsible for removing the prenyl anchor from the A-type lamin protein is the type I prenyl protease Zmpste24 (Barrowman and Michaelis 2009). This enzyme functions as a zinc metalloprotease and is highly conserved, and it was discovered by its ability to complement the homologous function in yeast (Tam et al. 1998). "
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    ABSTRACT: Many proteins require the addition of a hydrophobic prenyl anchor (prenylation) for proper trafficking and localization in the cell. Prenyl proteases play critical roles in modifying proteins for membrane anchorage. The type I prenyl protease has a defined function in yeast (Ste24p/Afc1p) where it modifies a mating pheromone, and in humans (Zmpste24) where it has been implicated in a disease of premature aging. Despite these apparently very different biological processes, the type I prenyl protease gene is highly conserved, encoded by a single gene in a wide range of animal and plant groups. A notable exception is Drosophila melanogaster, where the gene encoding the type I prenyl protease has undergone an unprecedented series of duplications in the genome, resulting in five distinct paralogs, three of which are organized in a tandem array, and demonstrate high conservation, particularly in the vicinity of the active site of the enzyme. We have undertaken targeted deletion to remove the three tandem paralogs from the genome. The result is a male fertility defect, manifesting late in spermatogenesis. Our results also show that the ancestral type I prenyl protease gene in Drosophila is under strong purifying selection, while the more recent replicates are evolving rapidly. Our rescue data support a role for the rapidly evolving tandem paralogs in the male germline. We propose that potential targets for the male-specific type I prenyl proteases include proteins involved in the very dramatic cytoskeletal remodeling events required for spermatid maturation.
    G3-Genes Genomes Genetics 06/2012; 2(6):629-42. DOI:10.1534/g3.112.002188 · 3.20 Impact Factor
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    • "Prelamin A is the only known mammalian substrate for ZMPSTE24. Interestingly, ZMPSTE24 plays dual roles in lamin A maturation, both in 1) AAX'ing (endoproteolyis of the CAAX motif; Figure 1A, step 2), a role in which it is functionally redundant with RCE1, and in 2) tail cleavage, a role in which ZMPSTE24 is uniquely required (Figure 1A, step 4) [5], [13], [14]. "
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    ABSTRACT: The proteolytic maturation of the nuclear protein lamin A by the zinc metalloprotease ZMPSTE24 is critical for human health. The lamin A precursor, prelamin A, undergoes a multi-step maturation process that includes CAAX processing (farnesylation, proteolysis and carboxylmethylation of the C-terminal CAAX motif), followed by ZMPSTE24-mediated cleavage of the last 15 amino acids, including the modified C-terminus. Failure to cleave the prelamin A "tail", due to mutations in either prelamin A or ZMPSTE24, results in a permanently prenylated form of prelamin A that underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) and related progeroid disorders. Here we have investigated the features of the prelamin A substrate that are required for efficient cleavage by ZMPSTE24. We find that the C-terminal 41 amino acids of prelamin A contain sufficient context to allow cleavage of the tail by ZMPSTE24. We have identified several mutations in amino acids immediately surrounding the cleavage site (between Y646 and L647) that interfere with efficient cleavage of the prelamin A tail; these mutations include R644C, L648A and N650A, in addition to the previously reported L647R. Our data suggests that 9 of the 15 residues within the cleaved tail that lie immediately upstream of the CAAX motif are not critical for ZMPSTE24-mediated cleavage, as they can be replaced by the 9 amino acid HA epitope. However, duplication of the same 9 amino acids (to increase the distance between the prenyl group and the cleavage site) impairs the ability of ZMPSTE24 to cleave prelamin A. Our data reveals amino acid preferences flanking the ZMPSTE24 cleavage site of prelamin A and suggests that spacing from the farnesyl-cysteine to the cleavage site is important for optimal ZMPSTE24 cleavage. These studies begin to elucidate the substrate requirements of an enzyme activity critical to human health and longevity.
    PLoS ONE 02/2012; 7(2):e32120. DOI:10.1371/journal.pone.0032120 · 3.23 Impact Factor
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