A-type lamins: Guardians of the soma?

Hutchison, Chris; Worman, Howard J.

doi:10.1038/ncb1104-1062

Cited by 196 publications

(178 citation statements)

References 89 publications

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“…The mutation responsible for HGPS was recently mapped to the LMNA gene, which encodes lamin A and the splice variant lamin C (2, 3). These proteins, together with lamin B, form the nuclear lamina, a protein meshwork underlying the inner nuclear envelope that helps to maintain nuclear architecture and that interacts with chromatin and regulators of transcription (4,5).…”

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confidence: 99%

Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome

Mallampalli

Huyer

Bendale

et al. 2005

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

186

154

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Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging disease resulting from a mutation in the LMNA gene, which encodes nuclear lamins A and C. Lamin A is synthesized as a precursor (prelamin A) with a C-terminal CaaX motif that undergoes farnesylation, endoproteolytic cleavage, and carboxylmethylation. Prelamin A is subsequently internally cleaved by the zinc metalloprotease Ste24 (Zmpste24) protease, which removes the 15 C-terminal amino acids, including the CaaX modifications, to yield mature lamin A. HGPS results from a dominant mutant form of prelamin A (progerin) that has an internal deletion of 50 aa near the C terminus that includes the Zmpste24 cleavage site and blocks removal of the CaaX-modified C terminus. Fibroblasts from HGPS patients have aberrant nuclei with irregular shapes, which we hypothesize result from the abnormal persistence of the farnesyl and͞or carboxylmethyl CaaX modifications on progerin. If this hypothesis is correct, inhibition of CaaX modification by mutation or pharmacological treatment should alleviate the nuclear morphology defect. Consistent with our hypothesis, we find that expression in HeLa cells of GFP-progerin or an uncleavable form of prelamin A with a Zmpste24 cleavage site mutation induces the formation of abnormal nuclei similar to those in HGPS fibroblasts. Strikingly, inhibition of farnesylation pharmacologically with the farnesyl transferase inhibitor rac-R115777 or mutationally by alteration of the CaaX motif dramatically reverses the abnormal nuclear morphology. These results suggest that farnesyl transferase inhibitors represent a possible therapeutic option for individuals with HGPS and͞or other laminopathies due to Zmpste24 processing defects.aging ͉ posttranslational processing ͉ laminopathy ͉ Ste24p ͉ Zarnestra

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confidence: 99%

Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome

Mallampalli

Huyer

Bendale

et al. 2005

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

186

154

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“…B-type lamins, encoded by two human genes (LMNB1 and LMNB2), are essential for cell viability. In contrast, the four A-type lamins (A, C, C2, and A⌬10), representing splicing isoforms of the LMNA gene, are dispensable for viability of individual cells but have crucial functions in tissue organization after birth (3, 4).In addition to the lamins, the nuclear lamina contains a number of integral membrane proteins of the inner nuclear membrane, the best characterized of which are the Lamin B receptor, Lamina-associated polypeptide (LAP), 4 and the three LEM domain-containing proteins LAP2␤, emerin and MAN1 (5, 6). All these proteins interact with lamin A/C and/or B and contribute to anchorage of the nuclear membrane to the lamina.…”

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confidence: 99%

“…In addition to the lamins, the nuclear lamina contains a number of integral membrane proteins of the inner nuclear membrane, the best characterized of which are the Lamin B receptor, Lamina-associated polypeptide (LAP), 4 and the three LEM domain-containing proteins LAP2␤, emerin and MAN1 (5, 6). All these proteins interact with lamin A/C and/or B and contribute to anchorage of the nuclear membrane to the lamina.…”

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confidence: 99%

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Lamina-associated Polypeptide 2-α Forms Homo-trimers via Its C Terminus, and Oligomerization Is Unaffected by a Disease-causing Mutation

Snyers

Vlcek

Dechat

et al. 2007

Journal of Biological Chemistry

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The nucleoplasmic protein, Lamina-associated polypeptide (LAP) 2␣, is one of six alternatively spliced products of the LAP2gene, which share a common N-terminal region. In contrast to the other isoforms, which also share most of their C termini, LAP2␣ has a large unique C-terminal region that contains binding sites for chromatin, A-type lamins, and retinoblastoma protein. By immunoprecipitation analyses of LAP2␣ complexes from cells expressing differently tagged LAP2␣ proteins and fragments, we demonstrate that LAP2␣ forms higher order structures containing multiple LAP2␣ molecules in vivo and that complex formation is mediated by the C terminus. Solid phase binding assays using recombinant and in vitro translated LAP2␣ fragments showed direct interactions of LAP2␣ C termini. Cross-linking of LAP2␣ complexes and multiangle light scattering of purified LAP2␣ revealed the existence of stable homo-trimers in vivo and in vitro. Finally, we show that, in contrast to the LAP2␣-lamin A interaction, its self-association is not affected by a disease-linked single point mutation in the LAP2␣ C terminus.The nuclear envelope comprises the inner and outer nuclear membranes, the nuclear pore complexes, and the nuclear lamina, which underlies the inner nuclear membrane (1, 2). The nuclear lamina is the major structural framework in the nucleus of multicellular eukaryotes and is composed of a filamentous meshwork of type V intermediate filament proteins, the lamins. B-type lamins, encoded by two human genes (LMNB1 and LMNB2), are essential for cell viability. In contrast, the four A-type lamins (A, C, C2, and A⌬10), representing splicing isoforms of the LMNA gene, are dispensable for viability of individual cells but have crucial functions in tissue organization after birth (3, 4).In addition to the lamins, the nuclear lamina contains a number of integral membrane proteins of the inner nuclear membrane, the best characterized of which are the Lamin B receptor, Lamina-associated polypeptide (LAP), 4 and the three LEM domain-containing proteins LAP2␤, emerin and MAN1 (5, 6). All these proteins interact with lamin A/C and/or B and contribute to anchorage of the nuclear membrane to the lamina. The LEM domain, a conserved 40-amino-acid motif located near the N terminus of the LEM family proteins, interacts with the DNA-binding protein barrier-to-autointegration factor (BAF) and mediates the binding of these proteins to chromatin (7). In LAP2 proteins, a LEM-like segment at the very N terminus has been shown to interact with DNA directly (8).The family of LAP2 proteins includes six alternatively spliced isoforms derived from the same gene (9). Most LAP2 isoforms are closely related structurally and functionally and are localized to the inner nuclear membrane, such as LAP2␤. In contrast, LAP2␣ shares only the N-terminal 187 amino acids with the other isoforms, including the LEM and LEM-like domains, but otherwise possesses a unique 506-amino-acid C-terminal region without a transmembrane domain (see Fig. 1A), encoded by one large exon...

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“…Lamina is a meshwork of nuclear-specific type V intermediate filaments (IF) called lamins, associated with the nuclear membrane, either directly or through interactions with membrane-bound proteins [2,3,[5][6][7][8]. As a basic structural unit, lamins form coiled-coil dimers that associate longitudinally to form polar head-to-tail polymers [2,[9][10][11]. According to their primary sequence, biochemical properties and expression patterns, lamins have been classified as A-and B-type, which are differentially expressed in cells.…”

Section: Introductionmentioning

confidence: 99%

Structures of the lamin A/C R335W and E347K mutants: Implications for dilated cardiolaminopathies

Bollati

Barbiroli

Favalli

et al. 2012

Biochemical and Biophysical Research Communications

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a b s t r a c tDilated cardiomyopathy (DCM) is a condition whereby the normal muscular function of the myocardium is altered by specific or multiple aetiologies. About 25-35% of DCM patients show familial forms of the disease, with most mutations affecting genes encoding cytoskeletal proteins. Most of the DCM-related mutations fall in the Lamin AC gene, in particular in the Coil2B domain of the encoded protein. In this context, we focussed our studies on the crystal structures of two lamin Coil2B domain mutants (R335W and E347K). Both R335 and E347 are higly conserved residues whose substitution has little effects on the Coil2B domain three-dimensional structure; we can thus hypothesize that the mutations may interfere with the binding of components within the nuclear lamina, or of nuclear factors, that have been proposed to interact/associate with lamin A/C.

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A-type lamins: Guardians of the soma?

Cited by 196 publications

References 89 publications

Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome

Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome

Lamina-associated Polypeptide 2-α Forms Homo-trimers via Its C Terminus, and Oligomerization Is Unaffected by a Disease-causing Mutation

Structures of the lamin A/C R335W and E347K mutants: Implications for dilated cardiolaminopathies

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