The CaaX motif is required for isoprenylation, carboxyl methylation, and nuclear membrane association of lamin B2.

Kitten, Gregory T.; Nigg, Erich A.

doi:10.1083/jcb.113.1.13

Cited by 183 publications

(127 citation statements)

References 69 publications

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“…Earlier site-directed mutagenesis studies suggested that farnesylation is important for the targeting of both lamin B1 and lamin B2 to the nuclear envelope (35,36). Thus, before embarking on the mouse studies, it would have been impossible to predict that abolishing the farnesylation of lamin B1 and lamin B2 would result in different phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…9). Lamin B1's hydrophobic farnesyl lipid anchor is almost certainly embedded in the inner nuclear membrane (43) and functions to affix the nuclear lamina to the nuclear membranes (35,36). In Lmnb1 CS/CS mice, the cytoplasmic motors likely remain quite effective in pulling the LINC complex/nuclear lamina toward the centrosome in the leading edge of the cell.…”

Section: Discussionmentioning

confidence: 99%

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Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Jung¹,

Nobumori²,

Goulbourne³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1-but not lamin B2-is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.genetically modified mouse models T he nuclear lamina is an intermediate filament meshwork that lies beneath the inner nuclear membrane. This lamina provides structural support for the nucleus and also interacts with nuclear proteins and chromatin, thereby affecting many functions within the cell nucleus (1, 2). In mammals, the main protein components of the nuclear lamina are lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins).Both B-type lamins and prelamin A (the precursor of lamin A) terminate with a CaaX motif, which triggers three posttranslational modifications (3-5): farnesylation of the carboxyl-terminal cysteine (the "C" in the CaaX motif) (6), endoproteolytic cleavage of the last three amino acids (the -aaX) (7,8), and carboxyl methylation of the newly exposed farnesylcysteine (9, 10). Prelamin A undergoes a second endoproteolytic cleavage event, mediated by zinc metalloproteinase STE24 (ZMPSTE24), which removes 15 additional amino acids from the carboxyl terminus, including the farnesylcysteine methyl ester (11)(12)(13)(14). Lamins B1 and B2 do not undergo the second cleavage step and therefore retain their farnesyl lipid anchor.The discovery that Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation yielding an internally truncated farnesyl-prelamin A (15) has focused interest in the farnesylation of nuclear lamins. This interest has been fueled by the finding that disease phenotypes in mouse models of HGPS could be ameliorated by blocking protein farnesylation with a protein farnesyltransferase inhibitor (FTI) (16)(17)(18)(19). Most recently, children with HGPS seemed to show a positive response to FTI treatment (20).The prospect of using an FTI to treat children with HGPS naturally raises the issue of the importance of protein farnesylation for lamin B1 and lamin B2. The B-type lamins are expressed in all mammalian cells and have been h...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Jung¹,

Nobumori²,

Goulbourne³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…A nuclear localization signal and a CaaX box at the carboxyl terminus are necessary to the latter process [15,16,28,29]. The CaaX motif (C: cysteine, a: an aliphatic amino acid, X: any amino acid) is a substrate for 3 successive post-translational modifications (isoprenylation of the cysteine, proteolytic removal of three carboxyl terminal acids; and carboxyl-methylation of the isoprenylated cysteine).…”

Section: Nuclei Assembled In Vitro and Their Lamina Componentsmentioning

confidence: 99%

Observation of nuclei reassembled from demembranated Xenopus sperm nuclei and analysis of their lamina components

Jian¹,

Zhang²,

Zhai³

1994

Cell Res

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A cell-free preparation obtained from extracts of activated Xenopus laevis eggs induced chromatin decondensation and nuclear formation from demembranated Xenopus sperm nuclei. Electron microscopy revealed that the reassembled nucleus had a double-layered nuclear membrane, nuclear pore complexes, and decondensed chromatin etc. Indirect immunofluorescence analysis demonstrated the presence of lamina in newly assembled nuclei. Western-blotting results showed that lamin L II was present in egg extracts and in lamina of the reassembled nuclei which were previously reported to contain only egg derived lamin L III .

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“…Only the binding of some proteins to nucleic acids, be it sequence-specific or broadly selective, has been studied to some extent (Bandziulis et al, 1989;Van Holde, 1989;Churchill and Travers, 1991;Li and Bingham, 1991;Tafuri and Wolffe, 1993). Moreover, sequence requirements for the assembly of karyoskeletal proteins of the lamin group into a lamina associated with the inner nuclear membrane have been determined (Loewinger and McKeon, 1988;Holtz et al, 1989;Krohne et al, 1989;Kitten and Nigg, 1991;Smith and Blobel, 1993;Soullam and Worman, 1993;Meier and Georgatos, 1994).…”

Section: Introductionmentioning

confidence: 99%

Topogenesis of a nucleolar protein: determination of molecular segments directing nucleolar association.

Zirwes

Kouzmenko

Peters

et al. 1997

MBoC

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To identify the element(s) in nucleolar proteins which determine nucleolus-specific topogenesis, we have used different kinds of cDNA constructs encoding various chimeric combinations of mutants of the constitutive nucleolar protein N038 (B23): 1) with an amino terminally placed short "myc tag"; 2) with two different carboxyl terminally attached large a-helical coiled coil structures, the lamin A rod domain or the rod domain of vimentin; 3) with the sequence-related nucleoplasmic histone-binding protein nucleoplasmin; and 4) with the soluble cytoplasmic protein pyruvate kinase. To avoid the problem of formation of complexes with endogenous wild-type (wt) molecules and "piggyback" localization, special care was taken to secure that the mutants and chimeras used did not oligomerize as is typical of protein N038 (B23). Using microinjection and transfection of cultured cells, we found that the segment comprising the amino-terminal 123 amino acids (aa) alone was sufficient to effect nucleolar accumulation of the construct molecules, including the chimeras with the entire rod domains of lamin A and vimentin. However, when the amino-terminal 109 aa were deleted, the molecules still associated with the nucleolus. The results of further deletion experiments and of domain swaps with nucleoplasmin all point to the topogenic importance of two independent molecular regions located at both the amino-and carboxyl-terminal end. Our definition of dominant elements determining the nucleolar localization of protein N038 (B23) as well as of diverse nonnucleolar proteins will help to identify its local binding partner(s) and functions, the construction of probes examining other proteins or sequence elements within the nucleolar microenvironment, and the generation of cells with an altered nuclear architecture.

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The CaaX motif is required for isoprenylation, carboxyl methylation, and nuclear membrane association of lamin B2.

Cited by 183 publications

References 69 publications

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Observation of nuclei reassembled from demembranated Xenopus sperm nuclei and analysis of their lamina components

Topogenesis of a nucleolar protein: determination of molecular segments directing nucleolar association.

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