Cardiomyocyte Microtubules: Control of Mechanics, Transport, and Remodeling

2021 ◽  
Vol 84 (1) ◽  
Author(s):  
Keita Uchida ◽  
Emily A. Scarborough ◽  
Benjamin L. Prosser
Keyword(s):  
Posttranslational Modifications ◽  
Protein Translation ◽  
Calcium Handling ◽  
Annual Review ◽  
Publication Date ◽  
Microtubule Associated Proteins ◽  
New Concepts ◽  
Cardiomyocyte Contractility ◽  
Associated Proteins ◽  
Cytoskeletal Elements

Microtubules are essential cytoskeletal elements found in all eukaryotic cells. The structure and composition of microtubules regulate their function, and the dynamic remodeling of the network by posttranslational modifications and microtubule-associated proteins generates diverse populations of microtubules adapted for various contexts. In the cardiomyocyte, the microtubules must accommodate the unique challenges faced by a highly contractile, rigidly structured, and long-lasting cell. Through their canonical trafficking role and positioning of mRNA, proteins, and organelles, microtubules regulate essential cardiomyocyte functions such as electrical activity, calcium handling, protein translation, and growth. In a more specialized role, posttranslationally modified microtubules form load-bearing structures that regulate myocyte mechanics and mechanotransduction. Modified microtubules proliferate in cardiovascular diseases, creating stabilized resistive elements that impede cardiomyocyte contractility and contribute to contractile dysfunction. In this review, we highlight the most exciting new concepts emerging from recent studies into canonical and noncanonical roles of cardiomyocyte microtubules. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Intracellular Proadrenomedullin-Derived Peptides Decorate the Microtubules and Contribute to Cytoskeleton Function

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2888-2898 ◽  
Author(s):  
Dan L. Sackett ◽  
Laurent Ozbun ◽  
Enrique Zudaire ◽  
Lisa Wessner ◽  
John M. Chirgwin ◽  
...  
Keyword(s):  
Posttranslational Modifications ◽  
Morphological Changes ◽  
Microtubule Associated Proteins ◽  
Microtubule Stabilization ◽  
Gene Coding ◽  
Intracellular Compartments ◽  
Associated Proteins ◽  
G2 Phase ◽  
Interfering Rna

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are secretory hormones, but it is not unusual to find them in intracellular compartments. Using yeast-2 hybrid technology, we found interactions between AM and several microtubule-associated proteins (MAPs), and between PAMP and tubulin. Expression of fluorescent-tagged AM and PAMP as well as immunofluorescence for the native peptides showed a complete decoration of the microtubules and colocalization with other MAPs. PAMP, but not AM, bound to tubulin in vitro and destabilized tubulin polymerization. Down-regulation of the gene coding for both AM and PAMP through small interfering RNA technology resulted in morphological changes, microtubule stabilization, increase in posttranslational modifications of tubulin such as acetylation and detyrosination, reduction in cell motility, and partial arrest at the G2 phase of the cell cycle, when compared with cells transfected with the same vector carrying a scrambled sequence. These results show that PAMP is a novel MAP, whereas AM may be exerting more subtle effects in regulating cytoskeleton function.

Regulatory Themes and Variations by the Stress-Signaling Nucleotide Alarmones (p)ppGpp in Bacteria

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Brent W. Anderson ◽  
Danny K. Fung ◽  
Jue D. Wang
Keyword(s):  
Metabolic Regulation ◽  
Protein Translation ◽  
Annual Review ◽  
Publication Date ◽  
Stress Signaling ◽  
Nucleotide Synthesis ◽  
Evolutionary Diversification ◽  
Metabolic Remodeling ◽  
Emerging Themes ◽  
Metabolic Interconversion

Bacterial stress-signaling alarmones are important components of a protective network against diverse stresses such as nutrient starvation and antibiotic assault. pppGpp and ppGpp, collectively (p)ppGpp, have well-documented regulatory roles in gene expression and protein translation. Recent work has highlighted another key function of (p)ppGpp: inducing rapid and coordinated changes in cellular metabolism by regulating enzymatic activities, especially those involved in purine nucleotide synthesis. Failure of metabolic regulation by (p)ppGpp results in the loss of coordination between metabolic and macromolecular processes, leading to cellular toxicity. In this review, we document how (p)ppGpp and newly characterized nucleotides pGpp and (p)ppApp directly regulate these enzymatic targets for metabolic remodeling. We examine targets’ common determinants for alarmone interaction as well as their evolutionary diversification. We highlight classical and emerging themes in nucleotide signaling, including oligomerization and allostery along with metabolic interconversion and crosstalk, illustrating how they allow optimized bacterial adaptation to their environmental niches. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals The Yin and Yang of Histone Marks in Transcription

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Paul B. Talbert ◽  
Steven Henikoff
Keyword(s):  
Posttranslational Modifications ◽  
Human Genetics ◽  
Annual Review ◽  
Publication Date ◽  
Histone Marks ◽  
The Core ◽  
Core Histones ◽  
Yin And Yang ◽  
Transcriptional State ◽  
Histone Core

Nucleosomes wrap DNA and impede access for the machinery of transcription. The core histones that constitute nucleosomes are subject to a diversity of posttranslational modifications, or marks, that impact the transcription of genes. Their functions have sometimes been difficult to infer because the enzymes that write and read them are complex, multifunctional proteins. Here, we examine the evidence for the functions of marks and argue that the major marks perform a fairly small number of roles in either promoting transcription or preventing it. Acetylations and phosphorylations on the histone core disrupt histone-DNA contacts and/or destabilize nucleosomes to promote transcription. Ubiquitylations stimulate methylations that provide a scaffold for either the formation of silencing complexes or resistance to those complexes, and carry a memory of the transcriptional state. Tail phosphorylations deconstruct silencing complexes in particular contexts. We speculate that these fairly simple roles form the basis of transcriptional regulation by histone marks. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Cold Shock Response in Bacteria

2021 ◽  
Vol 55 (1) ◽  
Author(s):  
Yan Zhang ◽  
Carol A. Gross
Keyword(s):  
Protein Folding ◽  
Cold Shock ◽  
Temperature Drop ◽  
Protein Translation ◽  
Annual Review ◽  
Publication Date ◽  
Molecular Response ◽  
Natural Habitats ◽  
Cold Shock Response ◽  
Shock Response

Bacteria often encounter temperature fluctuations in their natural habitats and must adapt to survive. The molecular response of bacteria to sudden temperature upshift or downshift is termed the heat shock response (HSR) or the cold shock response (CSR), respectively. Unlike the HSR, which activates a dedicated transcription factor that predominantly copes with heat-induced protein folding stress, the CSR is mediated by a diverse set of inputs. This review provides a picture of our current understanding of the CSR across bacteria. The fundamental aspects of CSR involved in sensing and adapting to temperature drop, including regulation of membrane fluidity, protein folding, DNA topology, RNA metabolism, and protein translation, are discussed. Special emphasis is placed on recent findings of a CSR circuitry in Escherichia coli mediated by cold shock family proteins and RNase R that monitors and modulates messenger RNA structure to facilitate global translation recovery during acclimation. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Effects of tubulin acetylation and tubulin acetyltransferase binding on microtubule structure

2014 ◽  
Vol 25 (2) ◽  
pp. 257-266 ◽  
Author(s):  
Stuart C. Howes ◽  
Gregory M. Alushin ◽  
Toshinobu Shida ◽  
Maxence V. Nachury ◽  
Eva Nogales
Keyword(s):  
Posttranslational Modifications ◽  
Luminal Surface ◽  
Microtubule Associated Proteins ◽  
Interaction Sites ◽  
Tubulin Acetylation ◽  
Cryo Electron Microscopy ◽  
Site Of Action ◽  
Associated Proteins ◽  
Tubulin Structure ◽  
Microtubule Structure

Tubulin undergoes posttranslational modifications proposed to specify microtubule subpopulations for particular functions. Most of these modifications occur on the C-termini of tubulin and may directly affect the binding of microtubule-associated proteins (MAPs) or motors. Acetylation of Lys-40 on α-tubulin is unique in that it is located on the luminal surface of microtubules, away from the interaction sites of most MAPs and motors. We investigate whether acetylation alters the architecture of microtubules or the conformation of tubulin, using cryo–electron microscopy (cryo-EM). No significant changes are observed based on protofilament distributions or microtubule helical lattice parameters. Furthermore, no clear differences in tubulin structure are detected between cryo-EM reconstructions of maximally deacetylated or acetylated microtubules. Our results indicate that the effect of acetylation must be highly localized and affect interaction with proteins that bind directly to the lumen of the microtubule. We also investigate the interaction of the tubulin acetyltransferase, αTAT1, with microtubules and find that αTAT1 is able to interact with the outside of the microtubule, at least partly through the tubulin C-termini. Binding to the outside surface of the microtubule could facilitate access of αTAT1 to its luminal site of action if microtubules undergo lateral opening between protofilaments.

scholarly journals Copolymerization of two distinct tubulin isotypes during microtubule assembly in vitro.

1990 ◽  
Vol 110 (1) ◽  
pp. 97-104 ◽  
Author(s):  
H N Baker ◽  
S W Rothwell ◽  
W A Grasser ◽  
K T Wallis ◽  
D B Murphy
Keyword(s):  
Posttranslational Modifications ◽  
Microtubule Assembly ◽  
Homogeneous Distribution ◽  
Chicken Brain ◽  
Microtubule Associated Proteins ◽  
Tubulin Isotypes ◽  
Associated Proteins ◽  
Specific Activities

Cells contain multiple tubulin isotypes that are the products of different genes and posttranslational modifications. It has been proposed that tubulin isotypes become segregated into different classes of microtubules each adapted to specific activities and functions. To determine if mixtures of tubulin isotypes segregate into different classes of polymers in vitro, we used immunoelectron microscopy to examine the composition of microtubule copolymers that assembled from mixtures of purified tubulin subunits from chicken brain and erythrocytes, each of which has been shown to exhibit distinct assembly properties in vitro. We observed that (a) the two isotypes coassemble rapidly and efficiently despite the fact that each isotype exhibits its own unique biochemical and assembly properties; (b) at low monomer concentrations the ratio of tubulin isotypes changes along the lengths of elongating copolymers resulting in gradients in immuno-gold labeling; (c) two distinct classes of copolymers each containing a distinct ratio of isotypes assemble simultaneously in the same subunit mixture; and (d) subunits and polymers of different isotypes associate nearly equally well with each other, there being only a slight bias favoring interactions among subunits and polymers of the same isotype. The observations agree with previous studies on the homogeneous distribution of multiple isotypes within cells and suggest that if segregation of isotypes does occur in vivo, it is most likely directed by cell-specific microtubule-associated proteins (MAPs) or specialized intracellular conditions.

scholarly journals Measure Transportation and Statistical Decision Theory

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Marc Hallin
Keyword(s):  
Real Space ◽  
Statistical Decision Theory ◽  
Annual Review ◽  
Publication Date ◽  
Var Models ◽  
Statistical Decision ◽  
Distribution Free ◽  
The Real ◽  
Inference Problems ◽  
New Concepts

Unlike the real line, the real space, in dimension d ≥ 2, is not canonically ordered. As a consequence, extending to a multivariate context fundamental univariate statistical tools such as quantiles, signs, and ranks is anything but obvious. Tentative definitions have been proposed in the literature but do not enjoy the basic properties (e.g., distribution-freeness of ranks, their independence with respect to the order statistic, their independence with respect to signs) they are expected to satisfy. Based on measure transportation ideas, new concepts of distribution and quantile functions, ranks, and signs have been proposed recently that, unlike previous attempts, do satisfy these properties. These ranks, signs, and quantiles have been used, quite successfully, in several inference problems and have triggered, in a short span of time, a number of applications: fully distribution-free testing for multiple-output regression, MANOVA, and VAR models; R-estimation for VARMA parameters; distribution-free testing for vector independence; multiple-output quantile regression; nonlinear independent component analysis; and so on. Expected final online publication date for the Annual Review of Statistics, Volume 9 is March 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Microtubule-associated proteins-dependent colchicine stability of acetylated cold-labile brain microtubules from the Atlantic cod, Gadus morhua.

1991 ◽  
Vol 113 (2) ◽  
pp. 331-338 ◽  
Author(s):  
M Billger ◽  
E Strömberg ◽  
M Wallin
Keyword(s):  
Posttranslational Modifications ◽  
Gadus Morhua ◽  
Atlantic Cod ◽  
Bovine Brain ◽  
General Effect ◽  
Acetylated Tubulin ◽  
Microtubule Associated Proteins ◽  
Associated Proteins ◽  
The Stability ◽  
Brain Microtubules

Assembly of brain microtubule proteins isolated from the Atlantic cod, Gadus morhua, was found to be much less sensitive to colchicine than assembly of bovine brain microtubules, which was completely inhibited by low colchicine concentrations (10 microM). The degree of disassembly by colchicine was also less for cod microtubules. The lack of colchicine effect was not caused by a lower affinity of colchicine to cod tubulin, as colchicine bound to cod tubulin with a dissociation constant, Kd, and a binding ratio close to that of bovine tubulin. Cod brain tubulin was highly acetylated and mainly detyrosinated, as opposed to bovine tubulin. When cod tubulin, purified by means of phosphocellulose chromatography, was assembled by addition of DMSO in the absence of microtubule-associated proteins (MAPs), the microtubules became sensitive to low concentrations of colchicine. They were, however, slightly more stable to disassembly, indicating that posttranslational modifications induce a somewhat increased stability to colchicine. The stability was mainly MAPs dependent, as it increased markedly in the presence of MAPs. The stability was not caused by an extremely large amount of cod MAPs, since there were slightly less MAPs in cod than in bovine microtubules. When "hybrid" microtubules were assembled from cod tubulin and bovine MAPs, these microtubules became less sensitive to colchicine. This was not a general effect of MAPs, since bovine MAPs did not induce a colchicine stability of microtubules assembled from bovine tubulin. We can therefore conclude that MAPs can induce colchicine stability of colchicine labile acetylated tubulin.

scholarly journals Microtubule-Associated Proteins with Regulatory Functions by Day and Pathological Potency at Night

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 357
Author(s):  
Judit Oláh ◽  
Attila Lehotzky ◽  
Sándor Szunyogh ◽  
Tibor Szénási ◽  
Ferenc Orosz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Posttranslational Modifications ◽  
Therapeutic Drug ◽  
Microtubule Network ◽  
Microtubule Associated Proteins ◽  
Tubulin Acetylation ◽  
Associated Proteins ◽  
Regulatory Functions ◽  
Tubulin Polymerization Promoting Protein

The sensing, integrating, and coordinating features of the eukaryotic cells are achieved by the complex ultrastructural arrays and multifarious functions of the cytoskeleton, including the microtubule network. Microtubules play crucial roles achieved by their decoration with proteins/enzymes as well as by posttranslational modifications. This review focuses on the Tubulin Polymerization Promoting Protein (TPPP/p25), a new microtubule associated protein, on its “regulatory functions by day and pathological functions at night”. Physiologically, the moonlighting TPPP/p25 modulates the dynamics and stability of the microtubule network by bundling microtubules and enhancing the tubulin acetylation due to the inhibition of tubulin deacetylases. The optimal endogenous TPPP/p25 level is crucial for its physiological functions, to the differentiation of oligodendrocytes, which are the major constituents of the myelin sheath. Pathologically, TPPP/p25 forms toxic oligomers/aggregates with α-synuclein in neurons and oligodendrocytes in Parkinson’s disease and Multiple System Atrophy, respectively; and their complex is a potential therapeutic drug target. TPPP/p25-derived microtubule hyperacetylation counteracts uncontrolled cell division. All these issues reveal the anti-mitotic and α-synuclein aggregation-promoting potency of TPPP/p25, consistent with the finding that Parkinson’s disease patients have reduced risk for certain cancers.

Role of microtubule-associated proteins in the control of microtubule assembly

1995 ◽  
Vol 75 (4) ◽  
pp. 835-864 ◽  
Author(s):  
R. B. Maccioni ◽  
V. Cambiazo
Keyword(s):  
Posttranslational Modifications ◽  
Mammalian Cells ◽  
Intracellular Transport ◽  
Cell Types ◽  
Regulatory Elements ◽  
Microtubule Assembly ◽  
Specific Cell ◽  
Surface Receptors ◽  
Microtubule Associated Proteins ◽  
Associated Proteins

In eukaryotic cells, microtubules, actin, and intermediate filaments interact to form the cytoskeletal network involved in determination of cell architecture, intracellular transport, modulation of surface receptors, mitosis, cell motility, and differentiation. Cytoskeletal organization and dynamics depend on protein self-associations and interactions with regulatory elements such as microtubule-associated proteins (MAPs). The MAP family includes large proteins like MAP-1A, MAP-1B, MAP-1C, MAP-2, and MAP-4 and smaller components like tau and MAP-2C. This review focuses on relevant aspects of MAP function, with emphasis on their roles in modulating cytoskeletal interactions. In this context, MAP expression mechanisms and posttranslational modifications are also discussed. Microtubule-associated proteins have a rather widespread distribution among cells, but certain MAPs have been identified in specific cell types. Within single neurons, MAP-2 is dendritic while tau is preferentially an axonal protein. Their expression is developmentally regulated. Even though MAPs share a capacity to interact with the COOH-terminal tubulin domain, stabilize microtubules, and link them with other cytoskeletal polymers, they exhibit structural differences. However, MAP-2, MAP-4, and tau have common repetitive microtubule-binding motifs. Microtubule-associated proteins not only control cytoskeletal integrity, but they also appear to interact with highly structural elements of cells. Molecular biological approaches permitted localization of new MAPs in cultured mammalian cells and invertebrate organisms and other microtubule-interacting proteins that exhibit transient interactions with microtubules. The structural/functional aspects of several new MAP-like proteins in centrosomes and the mitotic spindle, functionally implicated in cell cycle events, are also analyzed.

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