scholarly journals Role of A-type lamins in signaling, transcription, and chromatin organization

2009 ◽  
Vol 187 (7) ◽  
pp. 945-957 ◽  
Author(s):  
Vicente Andrés ◽  
José M. González
Keyword(s):  
Striated Muscle ◽  
Protein Complexes ◽  
Complex Structure ◽  
Nuclear Lamina ◽  
Major Protein ◽  
Progeroid Syndromes ◽  
Neuronal Tissues ◽  
Associated Proteins ◽  
Health And Disease

A-type lamins (lamins A and C), encoded by the LMNA gene, are major protein constituents of the mammalian nuclear lamina, a complex structure that acts as a scaffold for protein complexes that regulate nuclear structure and functions. Interest in these proteins has increased in recent years with the discovery that LMNA mutations cause a variety of human diseases termed laminopathies, including progeroid syndromes and disorders that primarily affect striated muscle, adipose, bone, and neuronal tissues. In this review, we discuss recent research supporting the concept that lamin A/C and associated nuclear envelope proteins regulate gene expression in health and disease through interplay with signal transduction pathways, transcription factors, and chromatin-associated proteins.

scholarly journals Direct and indirect interactions promote complexes of the lipoprotein LbcA, the CtpA protease and its substrates, and other cell wall proteins in Pseudomonas aeruginosa

2021 ◽  
Author(s):  
Dolonchapa Chakraborty ◽  
Andrew J. Darwin
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Wall ◽  
Protein Complexes ◽  
Associated Proteins ◽  
Carboxyl Terminal ◽  
Multiple Species ◽  
Processing Protease ◽  
Enzyme Complexes

The Pseudomonas aeruginosa lipoprotein LbcA was discovered because it copurified with and promoted the activity of CtpA, a carboxyl-terminal processing protease (CTP) required for type III secretion system function, and for virulence in a mouse model of acute pneumonia. In this study we explored the role of LbcA by determining its effect on the proteome and its participation in protein complexes. lbcA and ctpA null mutations had strikingly similar effects on the proteome, suggesting that assisting CtpA might be the most impactful role of LbcA in the bacterial cell. Independent complexes containing LbcA and CtpA, or LbcA and substrate, were isolated from P. aeruginosa cells, indicating that LbcA facilitates proteolysis by recruiting the protease and its substrates independently. An unbiased examination of proteins that copurified with LbcA revealed an enrichment for proteins associated with the cell wall. One of these copurification partners was found to be a new CtpA substrate, and the first substrate that is not a peptidoglycan hydrolase. Many of the other LbcA copurification partners are known or predicted peptidoglycan hydrolases. However, some of these LbcA copurification partners were not cleaved by CtpA, and an in vitro assay revealed that while CtpA and all of its substrates bound to LbcA directly, these non-substrates did not. Subsequent experiments suggested that the non substrates might co-purify with LbcA by participating in multi-enzyme complexes containing LbcA-binding CtpA substrates. IMPORTANCE Carboxyl-terminal processing proteases (CTPs) are widely conserved and associated with the virulence of several bacteria, including CtpA in Pseudomonas aeruginosa . CtpA copurifies with the uncharacterized lipoprotein, LbcA. This study shows that the most impactful role of LbcA might be to promote CtpA-dependent proteolysis, and that it achieves this as a scaffold for CtpA and its substrates. It also reveals that LbcA copurification partners are enriched for cell wall-associated proteins, one of which is a novel CtpA substrate. Some of the LbcA copurification partners are not cleaved by CtpA, but might copurify with LbcA because they participate in multi-enzyme complexes containing CtpA substrates. These findings are important, because CTPs and their associated proteins affect peptidoglycan remodeling and virulence in multiple species.

scholarly journals Molecular Structure of Sarcomere-to-Membrane Attachment at M-Lines inC. elegansMuscle

2010 ◽  
Vol 2010 ◽  
pp. 1-9 ◽  
Author(s):  
Hiroshi Qadota ◽  
Guy M. Benian
Keyword(s):  
Muscle Cell ◽  
Striated Muscle ◽  
Cell Attachment ◽  
Protein Complexes ◽  
Focal Adhesions ◽  
C Elegans ◽  
Nonmuscle Cell ◽  
Attachment Structures ◽  
Associated Proteins ◽  
Attachment Proteins

C. elegansis an excellent model for studying nonmuscle cell focal adhesions and the analogous muscle cell attachment structures. In the major striated muscle of this nematode, all of the M-lines and the Z-disk analogs (dense bodies) are attached to the muscle cell membrane and underlying extracellular matrix. Accumulating at these sites are many proteins associated with integrin. We have found that nematode M-lines contain a set of protein complexes that link integrin-associated proteins to myosin thick filaments. We have also obtained evidence for intriguing additional functions for these muscle cell attachment proteins.

scholarly journals A lamin A/C variant causing striated muscle disease provides insights into filament organization

2021 ◽  
Vol 134 (6) ◽  
pp. jcs256156
Author(s):  
Rafael Kronenberg-Tenga ◽  
Meltem Tatli ◽  
Matthias Eibauer ◽  
Wei Wu ◽  
Ji-Yeon Shin ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Electron Tomography ◽  
Nuclear Lamina ◽  
Muscle Disease ◽  
Relative Reduction ◽  
Embryonic Fibroblasts ◽  
Thick Filaments ◽  
Cryo Electron Tomography ◽  
Associated Proteins

ABSTRACTThe LMNA gene encodes the A-type lamins, which polymerize into ∼3.5-nm-thick filaments and, together with B-type lamins and associated proteins, form the nuclear lamina. Mutations in LMNA cause a wide variety of pathologies. In this study, we analyzed the nuclear lamina of embryonic fibroblasts from LmnaH222P/H222P mice, which develop cardiomyopathy and muscular dystrophy. Although the organization of the lamina appeared unaltered, there were changes in chromatin and B-type lamin expression. An increase in nuclear size and consequently a relative reduction in heterochromatin near the lamina allowed for a higher resolution structural analysis of lamin filaments using cryo-electron tomography. This was most apparent when visualizing lamin filaments in situ and using a nuclear extraction protocol. Averaging of individual segments of filaments in LmnaH222P/H222P mouse fibroblasts resolved two polymers that constitute the mature filaments. Our findings provide better views of the organization of lamin filaments and the effect of a striated muscle disease-causing mutation on nuclear structure.

The cytoskeleton of digestive epithelia in health and disease

1999 ◽  
Vol 277 (6) ◽  
pp. G1108-G1137 ◽  
Author(s):  
Nam-On Ku ◽  
Xiangjun Zhou ◽  
Diana M. Toivola ◽  
M. Bishr Omary
Keyword(s):  
Functional Integration ◽  
Major Protein ◽  
Protein Families ◽  
Therapeutic Modalities ◽  
Cell Functions ◽  
Digestive Diseases ◽  
Associated Proteins ◽  
Health And Disease ◽  
Biological Aspects ◽  
Cytoskeletal Elements

The mammalian cell cytoskeleton consists of a diverse group of fibrillar elements that play a pivotal role in mediating a number of digestive and nondigestive cell functions, including secretion, absorption, motility, mechanical integrity, and mitosis. The cytoskeleton of higher-eukaryotic cells consists of three highly abundant major protein families: microfilaments (MF), microtubules (MT), and intermediate filaments (IF), as well as a growing number of associated proteins. Within digestive epithelia, the prototype members of these three protein families are actins, tubulins, and keratins, respectively. This review highlights the important structural, regulatory, functional, and unique features of the three major cytoskeletal protein groups in digestive epithelia. The emerging exciting biological aspects of these protein groups are their involvement in cell signaling via direct or indirect interaction with a growing list of associated proteins (MF, MT, IF), the identification of several disease-causing mutations (IF, MF), the functional role that they play in protection from environmental stresses (IF), and their functional integration via several linker proteins that bridge two or potentially all three of these groups together. The use of agents that target specific cytoskeletal elements as therapeutic modalities for digestive diseases offers potential unique areas of intervention that remain to be fully explored.

scholarly journals Recent advances in understanding the role of lamins in health and disease

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2536 ◽  
Author(s):  
Sita Reddy ◽  
Lucio Comai
Keyword(s):  
Mechanical Stability ◽  
Genetic Diseases ◽  
Accelerated Aging ◽  
Nuclear Lamina ◽  
Active Role ◽  
Functional Consequences ◽  
Health And Disease ◽  
Consequences Of Disease ◽  
Hutchinson Gilford Progeria Syndrome

Lamins are major components of the nuclear lamina, a network of proteins that supports the nuclear envelope in metazoan cells. Over the past decade, biochemical studies have provided support for the view that lamins are not passive bystanders providing mechanical stability to the nucleus but play an active role in the organization of the genome and the function of fundamental nuclear processes. It has also become apparent that lamins are critical for human health, as a large number of mutations identified in the gene that encodes for A-type lamins are associated with tissue-specific and systemic genetic diseases, including the accelerated aging disorder known as Hutchinson-Gilford progeria syndrome. Recent years have witnessed great advances in our understanding of the role of lamins in the nucleus and the functional consequences of disease-associated A-type lamin mutations. Many of these findings have been presented in comprehensive reviews. In this mini-review, we discuss recent breakthroughs in the role of lamins in health and disease and what lies ahead in lamin research.

scholarly journals Analysis of biological networks in the endothelium with biomimetic microsystem platform

2019 ◽  
Vol 317 (3) ◽  
pp. L392-L401 ◽  
Author(s):  
Kevin Kruse ◽  
Jeff Klomp ◽  
Mitchell Sun ◽  
Zhang Chen ◽  
Dianicha Santana ◽  
...  
Keyword(s):  
Biological Networks ◽  
Protein Complexes ◽  
Single Point ◽  
Point Mutations ◽  
Cellular Processes ◽  
Signal Transduction Networks ◽  
Protein Interactome ◽  
Health And Disease ◽  
Cell To Cell Adhesion

Here we describe a novel method for studying the protein “interactome” in primary human cells and apply this method to investigate the effect of posttranslational protein modifications (PTMs) on the protein’s functions. We created a novel “biomimetic microsystem platform” (Bio-MSP) to isolate the protein complexes in primary cells by covalently attaching purified His-tagged proteins to a solid microscale support. Using this Bio-MSP, we have analyzed the interactomes of unphosphorylated and phosphomimetic end-binding protein-3 (EB3) in endothelial cells. Pathway analysis of these interactomes demonstrated the novel role of EB3 phosphorylation at serine 162 in regulating the protein’s function. We showed that phosphorylation “switches” the EB3 biological network to modulate cellular processes such as cell-to-cell adhesion whereas dephosphorylation of this site promotes cell proliferation. This novel technique provides a useful tool to study the role of PTMs or single point mutations in activating distinct signal transduction networks and thereby the biological function of the protein in health and disease.

scholarly journals Need for NAD+: Focus on Striated Muscle Laminopathies

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2248
Author(s):  
Déborah Cardoso ◽  
Antoine Muchir
Keyword(s):  
Nuclear Envelope ◽  
Striated Muscle ◽  
Current Knowledge ◽  
Nuclear Lamina ◽  
Genetic Mutations ◽  
Therapeutic Approaches ◽  
Gene Encoding ◽  
Differentiated Cells ◽  
Shed Light

Laminopathies are a heterogeneous group of rare diseases caused by genetic mutations in the LMNA gene, encoding A-type lamins. A-type lamins are nuclear envelope proteins which associate with B-type lamins to form the nuclear lamina, a meshwork underlying the inner nuclear envelope of differentiated cells. The laminopathies include lipodystrophies, progeroid phenotypes and striated muscle diseases. Research on striated muscle laminopathies in the recent years has provided novel perspectives on the role of the nuclear lamina and has shed light on the pathological consequences of altered nuclear lamina. The role of altered nicotinamide adenine dinucleotide (NAD+) in the physiopathology of striated muscle laminopathies has been recently highlighted. Here, we have summarized these findings and reviewed the current knowledge about NAD+ alteration in striated muscle laminopathies, providing potential therapeutic approaches.

scholarly journals Acetylation of N-terminus and two internal amino acids is dispensable for degradation of a protein that aberrantly engages the endoplasmic reticulum translocon

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3728 ◽  
Author(s):  
Sarah M. Engle ◽  
Justin J. Crowder ◽  
Sheldon G. Watts ◽  
Christopher J. Indovina ◽  
Samuel Z. Coffey ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Apolipoprotein B ◽  
Major Protein ◽  
Sequence Motifs ◽  
Complete Understanding ◽  
Post Translational Modifications ◽  
Lysine Residues ◽  
Associated Proteins

Conserved homologues of the Hrd1 ubiquitin ligase target for degradation proteins that persistently or aberrantly engage the endoplasmic reticulum translocon, including mammalian apolipoprotein B (apoB; the major protein component of low-density lipoproteins) and the artificial yeast protein Deg1-Sec62. A complete understanding of the molecular mechanism by which translocon-associated proteins are recognized and degraded may inform the development of therapeutic strategies for cholesterol-related pathologies. Both apoB and Deg1-Sec62 are extensively post-translationally modified. Mass spectrometry of a variant of Deg1-Sec62 revealed that the protein is acetylated at the N-terminal methionine and two internal lysine residues. N-terminal and internal acetylation regulates the degradation of a variety of unstable proteins. However, preventing N-terminal and internal acetylation had no detectable consequence for Hrd1-mediated proteolysis of Deg1-Sec62. Our data highlight the importance of empirically validating the role of post-translational modifications and sequence motifs on protein degradation, even when such elements have previously been demonstrated sufficient to destine other proteins for destruction.

scholarly journals PWWP INTERACTOR OF POLYCOMBS (PWO1) links PcG-mediated gene repression to the nuclear lamina inArabidopsis

2017 ◽  
Author(s):  
Pawel Mikulski ◽  
Mareike L. Hohenstatt ◽  
Sara Farrona ◽  
Cezary Smaczniak ◽  
Kerstin Kaufmann ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Target Genes ◽  
Protein Complexes ◽  
Nuclear Lamina ◽  
Polycomb Group ◽  
Gene Repression ◽  
Polycomb Repressive Complex 2 ◽  
Peripheral Protein ◽  
Wide Range ◽  
Associated Proteins

AbstractPolycomb group (PcG) proteins facilitate chromatin-mediated gene repression through the modification of histone tails in a wide range of eukaryotes, including plants and animals. One of the PcG protein complexes, Polycomb Repressive Complex 2 (PRC2), promotes repressive chromatin formation via tri-methylation of lysine-27 on histone H3 (H3K27me3). The animal PRC2 is implicated in impacting subnuclear distribution of chromatin as its complex components and H3K27me3 are functionally connected with the nuclear lamina (NL) - a peripheral protein mesh that resides underneath the inner nuclear membrane (INM) and consists of lamins and lamina-associated proteins. In contrast to animals, NL in plants has an atypical structure and its association with PRC2-mediated gene repression is largely unknown. Here, we present a connection between lamin-like protein, CROWDED NUCLEI 1 (CRWN1), and a novel PRC2-associated component, PWWP INTERACTOR OF POLYCOMBS 1 (PWO1), inArabidopsis thaliana. We show that PWO1 and CRWN1 proteins associate physically with each other, act in the same pathway to maintain nuclear morphology and control expression of similar set of target genes. Moreover, we demonstrate that PWO1 proteins form speckle-like foci located partially at the subnuclear periphery inNicotiana benthamianaandArabidopsis thaliana. Ultimately, as CRWN1 and PWO1 are plant-specific, our results argue that plants developed an equivalent, rather than homologous, mechanism of linking PRC2-mediated chromatin repression and nuclear lamina.

scholarly journals What is the role of lipid membrane-embedded quinones in ATP-synthesis? Chemiosmotic Q-cycle versus murburn reaction perspective

2020 ◽  
Author(s):  
Kelath Murali Manoj ◽  
Daniel Andrew Gideon ◽  
Abhinav Parashar
Keyword(s):  
Lipid Membranes ◽  
Lipid Membrane ◽  
Protein Complexes ◽  
Atp Synthesis ◽  
Structural Features ◽  
E Coli ◽  
Q Cycle ◽  
Transport Chain ◽  
Associated Proteins

Quinones are found in the lipid-membranes of prokaryotes like E. coli and cyanobacteria, and are also abundant in eukaryotic mitochondria and chloroplasts. They are intricately involved in the reaction mechanism of redox phosphorylations. In the Mitchellian chemiosmotic school of thought, membrane-lodged quinones are perceived as highly mobile conveyors of two-electron equivalents from the first leg of Electron Transport Chain (ETC) to the ‘second pit-stop’ of Cytochrome bc1 or b6f complex (CBC), where they undergo a regenerative ‘Q-cycle’. In Manoj’s murburn mechanism, the membrane-lodged quinones are perceived as one- or two- electron donors/acceptors, enabling charge separation and the CBC resets a one-electron paradigm via ‘turbo logic’. Herein, we compare various purviews of the two mechanistic schools with respect to: constraints in mobility, protons’ availability, binding of quinones with proteins, structural features of the protein complexes, energetics of reaction, overall reaction logic, etc. From various perspectives, it is concluded that the chemiosmotic Q-cycle is an untenable hypothesis. We project the murburn proposal as one rooted in thermodynamics/kinetics and which provides tangible structure-function correlations for the roles of quinones, lipid membrane and associated proteins.

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