scholarly journals Atomistic basis of microtubule dynamic instability assessed via multiscale modeling

2020 ◽  
Author(s):  
Mahya Hemmat ◽  
David J. Odde
Keyword(s):  
Multiscale Modeling ◽  
Dynamic Instability ◽  
Structural Information ◽  
Level Structure ◽  
Light And Electron Microscopy ◽  
Structural Data ◽  
Cellular Level ◽  
Atomic Level ◽  
Microtubule Dynamic ◽  
And Migration

AbstractMicrotubule “dynamic instability,” the abrupt switching from assembly to disassembly caused by the hydrolysis of GTP to GDP within the β subunit of the αβ-tubulin heterodimer, is necessary for vital cellular processes such as mitosis and migration. Despite existing high-resolution structural data, the key mechanochemical differences between the GTP and GDP states that mediate dynamic instability behavior remain unclear. Starting with a published atomic-level structure as an input, we used multiscale modeling to find that GTP hydrolysis results in both longitudinal bond weakening (~4 kBT) and an outward bending preference (~1.5 kBT) to both drive dynamic instability and give rise to the microtubule tip structures previously observed by light and electron microscopy. More generally, our study provides an example where atomic level structural information is used as the sole input to predict cellular level dynamics without parameter adjustment.

scholarly journals Atomistic Basis of Microtubule Dynamic Instability Assessed Via Multiscale Modeling

2021 ◽  
Author(s):  
Mahya Hemmat ◽  
David J. Odde
Keyword(s):  
Multiscale Modeling ◽  
Dynamic Instability ◽  
Structural Information ◽  
Level Structure ◽  
Light And Electron Microscopy ◽  
Structural Data ◽  
Cellular Level ◽  
Atomic Level ◽  
Microtubule Dynamic ◽  
And Migration

AbstractMicrotubule “dynamic instability,” the abrupt switching from assembly to disassembly caused by the hydrolysis of GTP to GDP within the β subunit of the αβ-tubulin heterodimer, is necessary for vital cellular processes such as mitosis and migration. Despite existing high-resolution structural data, the key mechanochemical differences between the GTP and GDP states that mediate dynamic instability behavior remain unclear. Starting with a published atomic-level structure as an input, we used multiscale modeling to find that GTP hydrolysis results in both longitudinal bond weakening (~ 4 kBT) and an outward bending preference (~ 1.5 kBT) to both drive dynamic instability and give rise to the microtubule tip structures previously observed by light and electron microscopy. More generally, our study provides an example where atomic level structural information is used as the sole input to predict cellular level dynamics without parameter adjustment.

Analysis of the Mechanism of Microtubule Dynamic Instability Using a UV Microbeam to Sever Elongating Microtubules

1988 ◽  
Vol 46 ◽  
pp. 122-123
Author(s):  
R.A Walker ◽  
S. Inoue ◽  
E.D. Salmon
Keyword(s):  
Dynamic Instability ◽  
Microtubule Dynamic ◽  
Gtp Hydrolysis ◽  
Abrupt Transition ◽  
Microtubule Associated Proteins ◽  
Asymmetrical Structure ◽  
Associated Proteins

Microtubules polymerized in vitro from tubulin purified free of microtubule-associated proteins exhibit dynamic instability (1,2,3). Free microtubule ends exist in persistent phases of elongation or rapid shortening with infrequent, but, abrupt transitions between these phases. The abrupt transition from elongation to rapid shortening is termed catastrophe and the abrupt transition from rapid shortening to elongation is termed rescue. A microtubule is an asymmetrical structure. The plus end grows faster than the minus end. The frequency of catastrophe of the plus end is somewhat greater than the minus end, while the frequency of rescue of the plus end in much lower than for the minus end (4).The mechanism of catastrophe is controversial, but for both the plus and minus microtubule ends, catastrophe is thought to be dependent on GTP hydrolysis. Microtubule elongation occurs by the association of tubulin-GTP subunits to the growing end. Sometime after incorporation into an elongating microtubule end, the GTP is hydrolyzed to GDP, yielding a core of tubulin-GDP capped by tubulin-GTP (“GTP-cap”).

scholarly journals Integrating genome sequence and structural data for statistical learning to predict transcription factor binding sites

2020 ◽  
Vol 48 (22) ◽  
pp. 12604-12617
Author(s):  
Pengpeng Long ◽  
Lu Zhang ◽  
Bin Huang ◽  
Quan Chen ◽  
Haiyan Liu
Keyword(s):  
Genome Sequence ◽  
Energy Function ◽  
Structural Information ◽  
Structural Data ◽  
P Values ◽  
A Genome ◽  
Z Scores ◽  
Transcription Regulators ◽  
Dna Specificity ◽  
Tetracycline Repressor

Abstract We report an approach to predict DNA specificity of the tetracycline repressor (TetR) family transcription regulators (TFRs). First, a genome sequence-based method was streamlined with quantitative P-values defined to filter out reliable predictions. Then, a framework was introduced to incorporate structural data and to train a statistical energy function to score the pairing between TFR and TFR binding site (TFBS) based on sequences. The predictions benchmarked against experiments, TFBSs for 29 out of 30 TFRs were correctly predicted by either the genome sequence-based or the statistical energy-based method. Using P-values or Z-scores as indicators, we estimate that 59.6% of TFRs are covered with relatively reliable predictions by at least one of the two methods, while only 28.7% are covered by the genome sequence-based method alone. Our approach predicts a large number of new TFBs which cannot be correctly retrieved from public databases such as FootprintDB. High-throughput experimental assays suggest that the statistical energy can model the TFBSs of a significant number of TFRs reliably. Thus the energy function may be applied to explore for new TFBSs in respective genomes. It is possible to extend our approach to other transcriptional factor families with sufficient structural information.

scholarly journals Temperature-jump studies of microtubule dynamic instability.

1988 ◽  
Vol 263 (21) ◽  
pp. 10344-10352
Author(s):  
M Caplow ◽  
J Shanks ◽  
R L Ruhlen
Keyword(s):  
Temperature Jump ◽  
Dynamic Instability ◽  
Microtubule Dynamic

scholarly journals Motile kinetochores and polar ejection forces dictate chromosome position on the vertebrate mitotic spindle

1994 ◽  
Vol 124 (3) ◽  
pp. 223-233 ◽  
Author(s):  
CL Rieder ◽  
ED Salmon
Keyword(s):  
Mitotic Spindle ◽  
Constant Velocity ◽  
Molecular Mechanisms ◽  
Dynamic Instability ◽  
Microtubule Dynamic ◽  
Pole Motion ◽  
Microtubule Motors ◽  
Chromosome Position ◽  
Pulling Forces

We argue that hypotheses for how chromosomes achieve a metaphase alignment, that are based solely on a tug-of-war between poleward pulling forces produced along the length of opposing kinetochore fibers, are no longer tenable for vertebrates. Instead, kinetochores move themselves and their attached chromosomes, poleward and away from the pole, on the ends of relatively stationary but shortening/elongating kinetochore fiber microtubules. Kinetochores are also "smart" in that they switch between persistent constant-velocity phases of poleward and away from the pole motion, both autonomously and in response to information within the spindle. Several molecular mechanisms may contribute to this directional instability including kinetochore-associated microtubule motors and kinetochore microtubule dynamic instability. The control of kinetochore directional instability, to allow for congression and anaphase, is likely mediated by a vectorial mechanism whose magnitude and orientation depend on the density and orientation or growth of polar microtubules. Polar microtubule arrays have been shown to resist chromosome poleward motion and to push chromosomes away from the pole. These "polar ejection forces" appear to play a key role in regulating kinetochore directional instability, and hence, positions achieved by chromosomes on the spindle.

scholarly journals Mechanisms Applied by Protein Inhibitors to Inhibit Cysteine Proteases

2021 ◽  
Vol 22 (3) ◽  
pp. 997
Author(s):  
Livija Tušar ◽  
Aleksandra Usenik ◽  
Boris Turk ◽  
Dušan Turk
Keyword(s):  
Binding Site ◽  
Structural Information ◽  
General Rule ◽  
Structural Data ◽  
Cysteine Proteases ◽  
Protein Inhibitors ◽  
Active Site Cleft ◽  
Living Organisms ◽  
And Control ◽  
Binding Mechanisms

Protein inhibitors of proteases are an important tool of nature to regulate and control proteolysis in living organisms under physiological and pathological conditions. In this review, we analyzed the mechanisms of inhibition of cysteine proteases on the basis of structural information and compiled kinetic data. The gathered structural data indicate that the protein fold is not a major obstacle for the evolution of a protease inhibitor. It appears that nature can convert almost any starting fold into an inhibitor of a protease. In addition, there appears to be no general rule governing the inhibitory mechanism. The structural data make it clear that the “lock and key” mechanism is a historical concept with limited validity. However, the analysis suggests that the shape of the active site cleft of proteases imposes some restraints. When the S1 binding site is shaped as a pocket buried in the structure of protease, inhibitors can apply substrate-like binding mechanisms. In contrast, when the S1 binding site is in part exposed to solvent, the substrate-like inhibition cannot be employed. It appears that all proteases, with the exception of papain-like proteases, belong to the first group of proteases. Finally, we show a number of examples and provide hints on how to engineer protein inhibitors.

Functional medial thickening and folding of the internal elastic lamina in coronary spasm

2011 ◽  
Vol 300 (2) ◽  
pp. H423-H430 ◽  
Author(s):  
Yasumi Uchida ◽  
Yasuto Uchida ◽  
Akimasa Matsuyama ◽  
Atsushi Koga ◽  
Yuko Maezawa ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Structural Changes ◽  
Light And Electron Microscopy ◽  
Coronary Spasm ◽  
Cellular Level ◽  
Internal Elastic Lamina ◽  
Circular Smooth Muscle ◽  
The Media ◽  
Medial Thickening ◽  
Elastic Lamina

Although there are a number of studies on vasospastic angina, the structural changes at the cellular level that occur in the coronary arterial wall during spasm are not well known. Coronary spasm was induced by brushing the coronary adventitia in nine anesthetized beagles, and structural changes in the spastic coronary segments were examined by light and electron microscopy, making comparisons with the adjacent nonspastic segments. The % diameter stenosis of the spastic segments as measured angiographically was 79.4 ± 12% (mean ± SD). Light microscopic changes in the spastic and nonspastic segments were as follows: medial thickness 1,512 vs. 392 μm ( P < 0.0001) and % diameter and % area stenoses of spastic segment 81.0% and 96.5%, respectively, indicating that spasm was induced by medial thickening. Circular smooth muscle cells (SMCs) in the media were arranged in parallel with the internal (IEL) and external (EEL) elastic lamina in nonspastic segments but radially rearranged in spastic segments. SMCs were classified by their patterns of connection to IEL into six types by electron microscopy. Of these, three contracted and pulled the IEL toward the EEL, causing folding of the IEL and waving of EEL resulting in thickening of the media and narrowing of the lumen. We conclude that coronary spasm was elicited by radial rearrangement of the medial SMCs due to their own contraction and resultant medial thickening and folding of IEL, creating a piston effect to narrow the lumen, i.e., spasm.

scholarly journals FINE STRUCTURAL OBSERVATIONS RELATING TO THE PRODUCTION OF COLOR BY THE IRIDOPHORES OF A LIZARD, ANOLIS CAROLINENSIS

1972 ◽  
Vol 53 (1) ◽  
pp. 38-52 ◽  
Author(s):  
Susannah T. Rohrlich ◽  
Keith R. Porter
Keyword(s):  
Thin Film ◽  
Electron Microscopy ◽  
Light And Electron Microscopy ◽  
Structural Data ◽  
Anolis Carolinensis ◽  
Dorsal Skin ◽  
Green Color ◽  
Structural Details ◽  
Thin Film Interference ◽  
Crystal Arrangement

This paper presents the results of light and electron microscopy done on iridophores in the dorsal skin of the lizard Anolis carolinensis. New fine-structural details are revealed, and their importance is discussed. Of some interest is the complex of filaments between crystalline sheets in the cell. It is proposed that this complex is involved in the arrangement of crystals into crystalline sheets, and that the crystal arrangement and spacing are critical for the production of the cells' blue-green color. Tyndall scattering and thin-film interference are discussed as possible explanations for iridophore color production in relation to the fine-structural data obtained.

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