Evidence for the Involvement of Lamins in Aging

Rodríguez, Sofía; Eriksson, Maria

doi:10.2174/1874609811003020081

Cited by 18 publications

(11 citation statements)

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“…Several progeroid disorders result from mutations in the genes encoding lamin A or ZMPSTE24 that interfere with the final proteolytic event that removes the modified tail [14], [17], [39]–[41]. The symptoms associated with these diseases range in severity and appear to correlate with the extent of the lamin A cleavage defect such that the greater the amount of uncleaved persistently prenylated prelamin A that accumulates, the more severe the disease.…”

Section: Discussionmentioning

confidence: 99%

Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24

Barrowman¹,

Hamblet²,

Kane³

et al. 2012

PLoS ONE

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BackgroundThe 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.Methodology/Principal FindingsHere 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.Conclusions/SignificanceOur 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.

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Section: Discussionmentioning

confidence: 99%

Requirements for Efficient Proteolytic Cleavage of Prelamin A by ZMPSTE24

Barrowman¹,

Hamblet²,

Kane³

et al. 2012

PLoS ONE

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“…The unexpected discovery that double-null pharynx (smooth) muscles had significantly reduced pumping activity is, to our knowledge, the first evidence that LEM-domain proteins are required in smooth muscle. Whether LEM-domain proteins are required in human smooth muscle is unknown and warrants testing, since it suggests genetic links to human smooth muscle disease and might provide molecular insight into the vascular smooth muscle pathology of Hutchinson-Gilford progeria syndrome, which is caused by severe mutations in LMNA (Rodríguez and Eriksson, 2010). Collectively, our findings support the possibility that human LEM2 mutations might influence or cause EDMD.…”

Section: Discussionmentioning

confidence: 99%

Ce-emerin and LEM-2: essential roles inCaenorhabditis elegansdevelopment, muscle function, and mitosis

Barkan

Zahand

Sharabi

et al. 2012

MBoC

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“…6 Although the pathophysiologic mechanisms involved in laminopathies are not fully understood, alterations in the posttranslational maturation of prelamin A are important pathogenic events. [7][8][9] Indeed, before being assembled in the nuclear lamina as mature lamin A, prelamin A undergoes several maturation steps including addition of a farnesyl group followed by a proteolytic cleavage by the metalloprotease Zmpste24. We and others have demonstrated that FPLD2 and metabolic laminopathies are associated with an abnormal accumulation of prelamin A, possibly due to misrecognition of the mutated protein by Zmpste24.…”

mentioning

confidence: 99%