The Supramolecular Organization of the C. elegans Nuclear Lamin Filament

Ben‐Harush, Kfir; Wiesel, Naama; Frenkiel-Krispin, Daphna; Moeller, Dorothee; Soreq, Eyal; Aebi, Ueli; Herrmann, Harald; Gruenbaum, Yosef; Medalia, Ohad

doi:10.1016/j.jmb.2008.12.024

Cited by 121 publications

(113 citation statements)

References 38 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…Although substituting lysine for glutamic acid at residue 145 does not alter dimer assembly as shown by AUC analysis, it does alter the normal alignment of protofilaments into filaments and PCs (2). In further support of this, a mutation in the corresponding site of Caenorhabditis elegans lamin (lmn-1), Q159K, alters the structure of in vitro assembled filaments (21,26).…”

Section: Discussionmentioning

confidence: 85%

“…Due to the thickness of PCs, we determined their structure in unfixed preparations embedded in amorphous ice by using cryo-electron tomography (cryo-ET) and 3-D image processing (21). Slices (x-y) of 60-nm-thick sections through reconstructed volumes of typical WT-LA and LA⌬50/progerin PCs showed regular arrays of protofilaments exhibiting the expected 24-nm repeats of dimeric tail domains along the ordered structures (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For TEM, cultured cells were processed as in (45) and for negative staining as in (46). Cryo-ET and structural analysis was carried out as in (21).…”

Section: Microscopymentioning

confidence: 99%

See 2 more Smart Citations

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

Taimen

Pfleghaar²,

Shimi

et al. 2009

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

Self Cite

194

215

View full text Add to dashboard Cite

Numerous mutations in the humancomprising the major structural components of the nuclear lamina, the fibrous meshwork underlying the inner nuclear membrane (1). They are major determinants of nuclear size and shape and are involved in essential functions such as DNA replication and transcription (1). Lamins A (LA) and C (LC) are alternatively spliced products of the LMNA gene, whereas lamins LB1 and LB2 are encoded by LMNB1 and LMNB2. Structurally, the lamins have a conserved central ␣-helical rod domain flanked by globular head and tail domains. The central rod is responsible for the formation of in-parallel and in-register coiled-coil dimers, the building blocks of lamin polymers. In vitro, lamin dimers form head-to-tail chains, which further interact laterally in an anti-parallel orientation to form highly ordered paracrystals (PCs) (2). However, little is known about the assembly of lamins into higher order structures in vivo.There are Ͼ250 mutations in human LMNA causing a wide range of diseases [for detail, see http//www.umd.be/LMNA/ and (3)]. Among these is the rare premature aging disease, Hutchinson-Gilford progeria syndrome (HGPS). HGPS children typically appear normal at birth, but show growth retardation before the age of 2 years. Further manifestations include loss of hair, lipodystrophy, sclerodermatous skin, osteolysis, and progressive atherosclerosis leading to death at an average age of 13 years due to myocardial infarcts and strokes (4). Most HGPS patients carry the 1824CϾT mutation (G608G), which activates a cryptic splice site resulting in the expression of LA with 50 amino acids deleted near its C terminus (LA⌬50/progerin) (5). As a result, LA⌬50/ progerin remains permanently farnesylated (6, 7), and its accumulation in patients' cells is correlated with the loss of heterochromatin and changes in histone methylation (1).In addition to 1824CϾT, there are 21 other LMNA mutations causing progeria (http://www.umd.be/LMNA/). Some of these are located in the central rod domain, where they could directly impact the assembly of lamins into dimers and higher order structures. Here, we have studied the alterations in nuclear architecture and chromatin organization in one of these mutations, 433GϾA (E145K), located in segment 1B of the central rod domain of LA/C (5). A patient bearing this mutation showed earlier onset cardiovascular defects, only partial loss of hair and ample s.c. fat (5). We show that fibroblasts derived from an E145K patient have severely misshapen nuclei and multiple defects in chromatin organization as reflected by centromere clustering and an abnormal distribution of telomeres throughout the cell cycle. These abnormalities are established during cell division as nuclei assemble in daughter cells. The results demonstrate that the nuclear changes in E145K progeria cells are significantly different from those seen in cells expressing LA⌬50/ progerin, and they also emphasize the essential role of lamins in establishing and maintaining nuclear architecture.

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization

Taimen

Pfleghaar²,

Shimi

et al. 2009

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

Self Cite

194

215

View full text Add to dashboard Cite

show abstract

“…The difference between the length of the rod domain and the axial repeat represents an overlap between adjacent rod domains [18] [19].…”

Section: From Dimers To Filamentsmentioning

confidence: 99%

Nuclear lamins: key regulators of nuclear structure and activities

Prokocimer¹,

Davidovich²,

Nissim-Rafinia³

et al. 2009

Journal of Cellular and Molecular Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…IF-like lamin filaments are composed of three to four tetrameric protofilaments. 19 These filaments form a meshwork apposed to the inner nuclear membrane that provides mechanical strength to nuclei and serves as a binding platform for the interaction with chromatin and many inner nuclear membrane proteins. 20 Lamins C2 and B3 show remarkable structural differences to their somatic counterparts.…”

Section: Introductionmentioning

confidence: 99%