The Last Twenty Residues in the Head Domain of Mouse Lamin A Contain Important Structural Elements for Formation of Head-to-Tail Polymers<i>in Vitro</i>

Isobe, Kazuhiro; Gohara, Rumi; Ueda, Toshihisa; Takasaki, Yozo; Ando, Shoji

doi:10.1271/bbb.60674

Cited by 25 publications

(25 citation statements)

References 35 publications

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“…Unlike cytoplasmic IFs, lamin dimers tend to form paracrystals in vitro rather than 10-nm filaments Herrmann and Foisner 2003;Melcer et al 2007). In addition to the central rod domain (Schirmer et al 2001;Strelkov et al 2004), it has been shown that the head and tail domains are also involved in lamin assembly (Sasse et al 1998;Stuurman et al 1998;Herrmann and Foisner 2003;Shumaker et al 2005;Isobe et al 2007). Although A-and B-type lamins appear to interact with each other in vitro (Georgatos et al 1988;Ye and Worman 1995;Schirmer and Gerace 2004), little is known about the composition and structure of lamin polymers within the lamina, and even less is known about their nucleoplasmic structures.…”

Section: Lamins As Structural Components Of the Nucleusmentioning

confidence: 99%

Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin

Dechat

Pfleghaar²,

Sengupta³

et al. 2008

Genes Dev.

867

879

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Over the past few years it has become evident that the intermediate filament proteins, the types A and B nuclear lamins, not only provide a structural framework for the nucleus, but are also essential for many aspects of normal nuclear function. Insights into lamin-related functions have been derived from studies of the remarkably large number of disease-causing mutations in the human lamin A gene. This review provides an up-to-date overview of the functions of nuclear lamins, emphasizing their roles in epigenetics, chromatin organization, DNA replication, transcription, and DNA repair. In addition, we discuss recent evidence supporting the importance of lamins in viral infections.In eukaryotic cells, chromatin is tightly packed in a highly organized fashion within a nucleus that is composed of two main compartments: the nucleoplasm and the nuclear envelope (NE). There are also subcompartments in the nucleus containing factors involved in essential nuclear functions such as DNA replication, transcription, and RNA splicing (Prasanth and Spector 2006;Spector 2006). The NE separates nuclear functions from cytoplasmic functions and at its inner surface it provides a docking site for chromatin. The major structural elements of the NE are the inner nuclear membrane (INM), the outer nuclear membrane (ONM), the nuclear pore complexes (NPCs), and the nuclear lamina. The lamina is comprised of a complex meshwork of proteins closely associated with the INM and attached to the periphery of NPCs and to chromatin (Fawcett 1966;Patrizi and Poger 1967;Aaronson and Blobel 1975). The main constituents of the lamina are the type V intermediate filament (IF) proteins, the nuclear lamins. Lamins are also found, in lower concentrations, distributed throughout the nucleoplasm. The organization of lamins at the nuclear periphery as well as within the nucleoplasm is influenced by numerous lamin-binding proteins (Dorner et al. 2007;Schirmer and Foisner 2007;Wagner and Krohne 2007).This review focuses on the role of nuclear lamins in the organization and regulation of chromatin in the interphase nucleus-specifically, the involvement of lamins in essential processes such as transcription, DNA replication, DNA repair, and various epigenetic phenomena involved in the regulation of euchromatin-heterochromatin transitions. Emphasis is also placed on the remarkable array of disease-causing mutations in the human lamin A gene, from which many of the most recent insights into lamin functions have been derived. In addition, we also discuss emerging ideas regarding the roles of lamins in viral infections. General properties of the nuclear laminsNuclear lamins were initially described as the major protein components of detergent-high salt resistant "lamina" fractions of rat liver and chicken erythrocyte nuclei (Aaronson and Blobel 1975;Gerace et al. 1978). Subsequently it was shown that they are members of the IF protein family (Aebi et al. 1986;Goldman et al. 1986;McKeon et al. 1986). Lamin genes are found in all metazoa examined to date, but are...

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Section: Lamins As Structural Components Of the Nucleusmentioning

confidence: 99%

Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin

Dechat

Pfleghaar²,

Sengupta³

et al. 2008

Genes Dev.

867

879

View full text Add to dashboard Cite

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“…This initial process is dependent on the head domain of lamin A (Isobe et al, 2007;Spann et al, 1997), thus proteins that bind with high affinity to the N-terminus of lamin A/C are expected to inhibit their assembly. Here, we have identified DARPins that specifically bind to the head domain and coil 1A (amino acids 1-62) of human lamin A, with Lys32 as an amino acid that is crucial for their binding ( Fig.…”

Section: Binding Of Darpins To the Head Domain Of Lamin A Inhibits Asmentioning

confidence: 99%

Altering lamina assembly identifies lamina-dependent and -independent functions for A-type lamins

Zwerger

Roschitzki-Voser

Zbinden

et al. 2015

Journal of Cell Science

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Lamins are intermediate filament proteins that form a fibrous meshwork, called the nuclear lamina, between the inner nuclear membrane and peripheral heterochromatin of metazoan cells. The assembly and incorporation of lamin A/C into the lamina, as well as their various functions, are still not well understood. Here, we employed designed ankyrin repeat proteins (DARPins) as new experimental tools for lamin research. We screened for DARPins that specifically bound to lamin A/C, and interfered with lamin assembly in vitro and with incorporation of lamin A/C into the native lamina in living cells. The selected DARPins inhibited lamin assembly and delocalized A-type lamins to the nucleoplasm without modifying lamin expression levels or the amino acid sequence. Using these lamin binders, we demonstrate the importance of proper integration of lamin A/C into the lamina for nuclear mechanical properties and nuclear envelope integrity. Finally, our study provides evidence for cell-type-specific differences in lamin functions.

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“…8, step 3) (14). Notably, Ser 22 is also a phosphorylation site of CDK1 (45). The CDK1 phosphorylation sites of the lamin types are part of conserved sequence stretches.…”

Section: Nec-associated Protein Kinases Pul97 and Pkc Trigger Regulatmentioning

confidence: 99%

“…The CDK1 phosphorylation sites of the lamin types are part of conserved sequence stretches. For lamin B, the respective phosphorylated residues are Ser 23 (lamin B1) and Ser 17 (lamin B2) (45). Lamins A and C are subject to alternative splicing of the LMNA gene and share the same N-terminal sequence, including the CDK1/pUL97 phosphorylation site.…”

Section: Nec-associated Protein Kinases Pul97 and Pkc Trigger Regulatmentioning

confidence: 99%

Novel Mode of Phosphorylation-triggered Reorganization of the Nuclear Lamina during Nuclear Egress of Human Cytomegalovirus

Milbradt

Webel

Auerochs

et al. 2010

Journal of Biological Chemistry

148

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The nucleocytoplasmic egress of viral capsids is a rate-limiting step in the replication of the human cytomegalovirus (HCMV). As reported recently, an HCMV-specific nuclear egress complex is composed of viral and cellular proteins, in particular protein kinases with the capacity to induce destabilization of the nuclear lamina. Viral protein kinase pUL97 and cellular protein kinase C (PKC) play important roles by phosphorylating several types of nuclear lamins. Using pUL97 mutants, we show that the lamin-phosphorylating activity of pUL97 is associated with a reorganization of nuclear lamin A/C. Either pUL97 or PKC has the potential to induce distinct punctate lamina-depleted areas at the periphery of the nuclear envelope, which were detectable in transiently transfected and HCMV-infected cells. Using recombinant HCMV, which produces green fluorescent protein-labeled viral capsids, the direct transition of viral capsids through these areas could be visualized. This process was sensitive to an inhibitor of pUL97/PKC activity. The pUL97-mediated phosphorylation of lamin A/C at Ser 22 generated a novel binding motif for the peptidyl-prolyl cis/trans-isomerase Pin1. In HCMV-infected fibroblasts, the physiological localization of Pin1 was altered, leading to recruitment of Pin1 to viral replication centers and to the nuclear lamina. The local increase in Pin1 peptidyl-prolyl cis/trans-isomerase activity may promote conformational modulation of lamins. Thus, we postulate a novel phosphorylation-triggered mechanism for the reorganization of the nuclear lamina in HCMVinfected cells. Human cytomegalovirus (HCMV)2 belongs to the ␤-herpesvirus subfamily, exhibiting worldwide distribution. When infecting immunocompetent individuals, HCMV possesses low pathogenicity, causing mainly asymptomatic infections. In immunocompromised or immunosuppressed hosts, HCMV infection can cause severe and even life-threatening diseases, including pneumonitis, retinitis, hepatitis, encephalitis, and gastroenteritis (1-3).HCMV replication is based on a nuclear phase, a characteristic of most DNA viruses. Transition from the nuclear to the cytoplasmic phase is determined by the nuclear exit of DNAfilled capsids budding through the inner nuclear membrane (INM) (4 -6). The site-specific budding of viral capsids through distinct locally occurring invaginations in the INM of HCMVinfected cells was clearly illustrated by Buser et al. (7) using electron microscopic analysis. The proteinaceous network of the nuclear lamina, underlying the INM, constitutes a major obstacle for the nuclear egress of capsids. Lamins, belonging to type V intermediate filament proteins, are the main constituents of the nuclear lamina and are grouped into A and B types. A-type lamins (A, C, A⌬10, and C2; collectively lamin A/C) result from alternative splicing of the LMNA gene. B-type lamins are encoded by the LMNB1 (B1) or LMNB2 (B2, B3) gene (8, 9). A major function of the nuclear lamina is to maintain the structure of the nuclear envelope. During mitosis, the nuclear lamin...

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The Last Twenty Residues in the Head Domain of Mouse Lamin A Contain Important Structural Elements for Formation of Head-to-Tail Polymersin Vitro

Cited by 25 publications

References 35 publications

Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin

Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin

Altering lamina assembly identifies lamina-dependent and -independent functions for A-type lamins

Novel Mode of Phosphorylation-triggered Reorganization of the Nuclear Lamina during Nuclear Egress of Human Cytomegalovirus

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