IP3 Receptor Plasticity Underlying Diverse Functions

In the body, extracellular stimuli produce inositol 1,4,5-trisphosphate (IP3), an intracellular chemical signal that binds to the IP3 receptor (IP3R) to release calcium ions (Ca2+) from the endoplasmic reticulum. In the past 40 years, the wide-ranging functions mediated by IP3R and its genetic defects causing a variety of disorders have been unveiled. Recent cryo-electron microscopy and X-ray crystallography have resolved IP3R structures and begun to integrate with concurrent functional studies, which can explicate IP3-dependent opening of Ca2+-conducting gates placed ∼90 Å away from IP3-binding sites and its regulation by Ca2+. This review highlights recent research progress on the IP3R structure and function. We also propose how protein plasticity within IP3R, which involves allosteric gating and assembly transformations accompanied by rapid and chronic structural changes, would enable it to regulate diverse functions at cellular microdomains in pathophysiological states.

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Influence of Ascorbic Acid on the Structure and Function of Alpha-2- macroglobulin: Investigations using Spectroscopic and Thermodynamic Techniques

Protein and Peptide Letters ◽

10.2174/0929866526666191002113525 ◽

2020 ◽

Vol 27 (3) ◽

pp. 201-209

Author(s):

Syed Saqib Ali ◽

Mohammad Khalid Zia ◽

Tooba Siddiqui ◽

Haseeb Ahsan ◽

Fahim Halim Khan

Keyword(s):

Ascorbic Acid ◽

Conformational Changes ◽

Structural Changes ◽

The Body ◽

Titration Calorimetry ◽

Spectroscopic Techniques ◽

Human Beings ◽

Plasma Ascorbic Acid ◽

Dietary Antioxidant ◽

And Function

Background: Ascorbic acid is a classic dietary antioxidant which plays an important role in the body of human beings. It is commonly found in various foods as well as taken as dietary supplement. Objective: The plasma ascorbic acid concentration may range from low, as in chronic or acute oxidative stress to high if delivered intravenously during cancer treatment. Sheep alpha-2- macroglobulin (α2M), a human α2M homologue is a large tetrameric glycoprotein of 630 kDa with antiproteinase activity, found in sheep’s blood. Methods: In the present study, the interaction of ascorbic acid with alpha-2-macroglobulin was explored in the presence of visible light by utilizing various spectroscopic techniques and isothermal titration calorimetry (ITC). Results: UV-vis and fluorescence spectroscopy suggests the formation of a complex between ascorbic acid and α2M apparent by increased absorbance and decreased fluorescence. Secondary structural changes in the α2M were investigated by CD and FT-IR spectroscopy. Our findings suggest the induction of subtle conformational changes in α2M induced by ascorbic acid. Thermodynamics signatures of ascorbic acid and α2M interaction indicate that the binding is an enthalpy-driven process. Conclusion: It is possible that ascorbic acid binds and compromises antiproteinase activity of α2M by inducing changes in the secondary structure of the protein.

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Structural Characterization of Carbonic Anhydrase VIII and Effects of Missense Single Nucleotide Variations to Protein Structure and Function

International Journal of Molecular Sciences ◽

10.3390/ijms21082764 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2764

Author(s):

Taremekedzwa Allan Sanyanga ◽

Özlem Tastan Bishop

Keyword(s):

Carbonic Anhydrase ◽

Binding Site ◽

Cross Correlation ◽

Structure And Function ◽

The Body ◽

Conformational Sampling ◽

Nucleotide Polymorphisms ◽

Ip3 Receptor ◽

Single Nucleotide ◽

And Function

Human carbonic anhydrase 8 (CA-VIII) is an acatalytic isoform of the α -CA family. Though the protein cannot hydrate CO2, CA-VIII is essential for calcium (Ca2+) homeostasis within the body, and achieves this by allosterically inhibiting the binding of inositol 1,4,5-triphosphate (IP3) to the IP3 receptor type 1 (ITPR1) protein. However, the mechanism of interaction of CA-VIII to ITPR1 is not well understood. In addition, functional defects to CA-VIII due to non-synonymous single nucleotide polymorphisms (nsSNVs) result in Ca2+ dysregulation and the development of the phenotypes such as cerebellar ataxia, mental retardation and disequilibrium syndrome 3 (CAMRQ3). The pathogenesis of CAMRQ3 is also not well understood. The structure and function of CA-VIII was characterised, and pathogenesis of CAMRQ3 investigated. Structural and functional characterisation of CA-VIII was conducted through SiteMap and CPORT to identify potential binding site residues. The effects of four pathogenic nsSNVs, S100A, S100P, G162R and R237Q, and two benign S100L and E109D variants on CA-VIII structure and function was then investigated using molecular dynamics (MD) simulations, dynamic cross correlation (DCC) and dynamic residue network (DRN) analysis. SiteMap and CPORT analyses identified 38 unique CA-VIII residues that could potentially bind to ITPR1. MD analysis revealed less conformational sampling within the variant proteins and highlighted potential increases to variant protein rigidity. Dynamic cross correlation (DCC) showed that wild-type (WT) protein residue motion is predominately anti-correlated, with variant proteins showing no correlation to greater residue correlation. DRN revealed variant-associated increases to the accessibility of the N-terminal binding site residues, which could have implications for associations with ITPR1, and further highlighted differences to the mechanism of benign and pathogenic variants. SNV presence is associated with a reduction to the usage of Trp37 in all variants, which has implications for CA-VIII stability. The differences to variant mechanisms can be further investigated to understand pathogenesis of CAMRQ3, enhancing precision medicine-related studies into CA-VIII.

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EFFECT OF NEONATAL HYPERTHYROIDISM ON PITUITARY STRUCTURE AND FUNCTION IN THE RAT

Journal of Endocrinology ◽

10.1677/joe.0.0290071 ◽

1964 ◽

Vol 29 (1) ◽

pp. 71-81 ◽

Cited By ~ 21

Author(s):

J. T. EAYRS ◽

R. L. HOLMES

Keyword(s):

Growth Hormone ◽

Structural Changes ◽

Statistical Significance ◽

Adult Life ◽

Hormone Treatment ◽

The Body ◽

Absolute Amount ◽

Pituitary Glands ◽

Neonatal Hyperthyroidism ◽

And Function

SUMMARY 1. Infant rats were given doses of l-triiodothyronine (T3) alone and combined with growth hormone during different periods of development. The effects of these treatments on the growth of the body and on the size and structure of the pituitary and thyroid glands have been examined. 2. At the dose levels given, the growth of the body and of the thyroid and pituitary glands was impaired. This impairment persisted in rats treated during the first 24 days of life and in animals in which treatment was confined to the 2–4th days long after injections had been discontinued and well into adult life. It did not persist in rats in which treatment was begun after the 14th day of age. 3. There were no obvious structural changes in the thyroid gland apart from its reduced size. All treatments were followed by pituitary changes characterized by a severe reduction, both in relative and absolute amount, of acidophilic tissue. There was only minor restoration of these changes after discontinuation of the hormone treatment except in rats injected after the 14th day in which recovery was complete. Changes in the amount of mucoid tissue (PAS-positive cells) were variable and generally of doubtful statistical significance. Non-secretory tissue was unaffected. 4. Administration of growth hormone in combination with T3 for the first 24 days of life did not give rise to effects which were noticeably different from those of giving T3 alone over the same period. 5. Possible explanations for these findings and the interrelationship between the pituitary changes and impaired growth are discussed.

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Contrasting effects of simulated microgravity with and without daily −Gx gravitation on structure and function of cerebral and mesenteric small arteries in rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00493.2009 ◽

2009 ◽

Vol 107 (6) ◽

pp. 1710-1721 ◽

Cited By ~ 31

Author(s):

Le-Jian Lin ◽

Fang Gao ◽

Yun-Gang Bai ◽

Jun-Xiang Bao ◽

Xiao-Feng Huang ◽

...

Keyword(s):

Structural Changes ◽

Cerebral Arteries ◽

Myogenic Tone ◽

Resistance Arteries ◽

Cross Sectional ◽

Small Arteries ◽

Functional Studies ◽

Cell Layers ◽

And Function

This study was designed to test the hypothesis that a 28-day tail suspension (SUS) could induce hypertrophy and enhanced myogenic and vasoconstrictor reactivity in middle cerebral arteries (MCAs), whereas atrophy and decreased myogenic and vasoconstrictor responses in mesenteric third-order arterioles (MSAs). Also, in addition to the functional enhancement in MCAs, structural changes in both kinds of arteries and functional decrement in MSAs could all be prevented by the intervention of daily 1-h dorsoventral (−Gx) gravitation by restoring to standing posture. To test this hypothesis, vessel diameters to pressure alterations and nonreceptor- and receptor-mediated agonists were determined using a pressure arteriograph with a procedure to measure in vivo length and decrease hysteresis of vessel segments and longitudinal middlemost sections of vessels fixed at maximally dilated state were examined using electron microscopy and histomorphometry. Functional studies showed that 28-day tail-suspended, head-down tilt (SUS) resulted in enhanced and decreased myogenic tone and vasoconstrictor responses, respectively, in MCAs and MSAs. Histomorphometric data revealed that SUS-induced hypertrophic changes in MCAs characterized by increases in thickness (T) and cross-sectional area (CSA) of the media and the number of vascular smooth-muscle-cell layers (NCL), whereas in MSAs, it induced decreases in medial CSA and T and NCL. Daily 1-h −Gx over 28 days can fully prevent these differential structural changes in both kinds of small arteries and the functional decrement in MSAs, but not the augmented myogenic tone and increased vasoreactivity in the MCAs. These findings have revealed special features of small resistance arteries during adaptation to microgravity with and without gravity-based countermeasure.

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Structural Conservation and Adaptation of the Bacterial Flagella Motor

Biomolecules ◽

10.3390/biom10111492 ◽

2020 ◽

Vol 10 (11) ◽

pp. 1492

Author(s):

Brittany L. Carroll ◽

Jun Liu

Keyword(s):

Electron Tomography ◽

X Ray ◽

Bacterial Flagella ◽

X Ray Crystallography ◽

Cryo Electron Microscopy ◽

Cryo Electron Tomography ◽

Flagellar Assembly ◽

Structural Conservation ◽

And Function ◽

Structural Insights

Many bacteria require flagella for the ability to move, survive, and cause infection. The flagellum is a complex nanomachine that has evolved to increase the fitness of each bacterium to diverse environments. Over several decades, molecular, biochemical, and structural insights into the flagella have led to a comprehensive understanding of the structure and function of this fascinating nanomachine. Notably, X-ray crystallography, cryo-electron microscopy (cryo-EM), and cryo-electron tomography (cryo-ET) have elucidated the flagella and their components to unprecedented resolution, gleaning insights into their structural conservation and adaptation. In this review, we focus on recent structural studies that have led to a mechanistic understanding of flagellar assembly, function, and evolution.

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Inositol hexakisphosphate is a critical regulator of Integrator assembly and function

10.1101/2021.09.14.460315 ◽

2021 ◽

Author(s):

Min-Han Lin ◽

Madeline K Jensen ◽

Nathan D Elrod ◽

Kai-Lieh Huang ◽

Eric J Wagner ◽

...

Keyword(s):

Binding Site ◽

Active Site ◽

Noncoding Rna ◽

Rna Cleavage ◽

Inositol Hexakisphosphate ◽

Functional Studies ◽

Cryo Electron Microscopy ◽

Stable Association ◽

And Function ◽

Cellular Control

Integrator has critical roles in noncoding RNA 3'-end processing as well as transcription attenuation of selected mRNAs. IntS11 is the endonuclease for RNA cleavage, as a part of the IntS4-IntS9-IntS11 complex (Integrator cleavage module, ICM). Our structure of the Drosophila ICM, determined by cryo-electron microscopy at 2.74 A resolution, unexpectedly revealed the stable association of an inositol hexakisphosphate (IP6) molecule. The binding site is located in a highly electropositive pocket at an interface among all three subunits of ICM, 55 A away from the IntS11 active site and generally conserved in other ICMs. IP6 binding is also confirmed in human ICM. Mutations of residues in this binding site or disruption of IP6 biosynthesis significantly reduced Integrator assembly and activity in snRNA 3'-end processing. Our structural and functional studies reveal that Integrator is subject to intricate cellular control and IP6 is a critical regulator of Integrator assembly and function in Drosophila, humans, and likely other organisms.

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Structural organization of signalling to and from IP3 receptors

Biochemical Society Transactions ◽

10.1042/bst20130205 ◽

2014 ◽

Vol 42 (1) ◽

pp. 63-70 ◽

Cited By ~ 23

Author(s):

Colin W. Taylor ◽

Stephen C. Tovey ◽

Ana M. Rossi ◽

Cristina I. Lopez Sanjurjo ◽

David L. Prole ◽

...

Keyword(s):

Spatial Organization ◽

Structural Changes ◽

Ryanodine Receptors ◽

Ip3 Receptors ◽

Ip3 Receptor ◽

Structural Determinants ◽

Extracellular Stimuli ◽

Selective Delivery ◽

Intracellular Targets ◽

Phosphate Groups

In the 30 years since IP3 (inositol 1,4,5-trisphosphate) was first shown to release Ca2+ from intracellular stores, the importance of spatially organized interactions within IP3-regulated signalling pathways has been universally recognized. Recent evidence that addresses three different levels of the structural determinants of IP3-evoked Ca2+ signalling is described in the present review. High-resolution structures of the N-terminal region of the IP3R (IP3 receptor) have established that the two essential phosphate groups of IP3 bind to opposite sides of the IP3-binding site, pulling its two domains together. This conformational change is proposed to disrupt an interaction between adjacent subunits within the tetrameric IP3R that normally holds the channel in a closed state. Similar structural changes are thought to allow gating of ryanodine receptors. cAMP increases the sensitivity of IP3Rs and thereby potentiates the Ca2+ signals evoked by receptors that stimulate IP3 formation. We speculate that both IP3 and cAMP are delivered to IP3Rs within signalling junctions, wherein the associated IP3Rs are exposed to a saturating concentration of either messenger. The concentration-dependent effects of extracellular stimuli come from recruitment of junctions rather than from a graded increase in the activity of individual junctions. IP3Rs within ‘IP3 junctions’ respond directly to receptors that stimulate phospholipase C, whereas extra-junctional IP3Rs are exposed to suboptimal concentrations of IP3 and open only when they are sensitized by cAMP. These results highlight the importance of selective delivery of diffusible messengers to IP3Rs. The spatial organization of IP3Rs also allows them to direct Ca2+ to specific intracellular targets that include other IP3Rs, mitochondria and Ca2+-regulated channels and enzymes. IP3Rs also interact functionally with lysosomes because Ca2+ released by IP3Rs, but not that entering cells via store-operated Ca2+ entry pathways, is selectively accumulated by lysosomes. This Ca2+ uptake shapes the Ca2+ signals evoked by IP3 and it may regulate lysosomal behaviour.

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Structural and functional studies of erythrocyte membrane-skeleton by single-cell and single-molecule techniques

Journal of Innovative Optical Health Sciences ◽

10.1142/s1793545818300045 ◽

2019 ◽

Vol 12 (01) ◽

pp. 1830004

Author(s):

Fulin Xing ◽

Fen Hu ◽

Jianyu Yang ◽

Leiting Pan ◽

Jingjun Xu

Keyword(s):

Mechanical Properties ◽

Single Cell ◽

Erythrocyte Membrane ◽

Single Molecule ◽

Membrane Skeleton ◽

Structure And Function ◽

The Body ◽

Extrusion Force ◽

Functional Studies ◽

And Function

As the indispensable oxygen-transporting cells, erythrocytes exhibit extreme deformability and amazing stability as they are subject to huge reversible shear stress and extrusion force during massive circulation in the body. The unique architecture of spectrin-actin-based membrane-skeleton is considered to be responsible for such excellent mechanical properties of erythrocytes. Although erythrocytes have been recognized for more than 300 years, myriad questions about membrane-skeleton constantly attract people’s attention. Here, we summarize the kinds of distinctive single-cell and single-molecule techniques that were used to investigate the structure and function of erythrocyte membrane-skeleton at macro and micro levels.

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Влияние климатогеографических факторов Севера на адаптивные реакции организма человека

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2020.01.147-154 ◽

2020 ◽

Author(s):

S.A. Ulyanovskaya ◽

D.V. Bazhenov ◽

V.G. Shestakova ◽

M.N. Kalinkin

Keyword(s):

Human Body ◽

Structural Changes ◽

Structure And Function ◽

The Body ◽

Stress Factors ◽

Endogenous Factors ◽

The North ◽

Study Results ◽

And Function ◽

Adaptive Reactions

В обзоре анализируется влияние климатогеографических факторов Севера на адаптивные реакции организма человека с позиций патологической физиологии. Основа адаптационных перестроек организма на Севере заключается в расширении физиологической нормы реакций и референсных пределов отдельных эндокринных и метаболических показателей. При выходе за пределы видовой нормы происходит снижение резервных возможностей организма, что приводит к патологии. Важную роль при этом играют внутригодовые колебания уровня гормонов, связанные с фотопериодикой. Ритмическая организация физиологических процессов имеет приспособительный характер, так как способствует подготовке и адаптации организма к условиям внешней среды в целях сохранения гомеостаза. Сезонные ритмы влияют на структуру и функцию всех систем организма человека. Многие патологические процессы в организме сопровождаются развитием десинхронозов. Рассогласование ритмов функционирования организма сопровождается нарушением исходной хроноструктурной организации физиологических реакций, что приводит не только к изменениям показателей функции эндокринной системы, но и к структурным изменениям в органах. Вопросы, рассмотренные в обзоре, отражают важность учета особенностей климатогеографических факторов Севера, приводящих к возникновению выраженных сдвигов в функционировании и структуре органов. Подтверждением вышесказанному является выявленный нами дисбаланс, в виде парциальной гипоплазии внешнесекреторного аппарата поджелудочной железы на фоне выраженного развития эндокринного компонента железы и стромы, это рассматривается как предпосылка для развития патологии. Анализ литературы показал также, что длительно действующий стрессовый фактор приводит к морфологической перестройке органов с адаптивными модификациями структуры.The review analyzes effects of climatic and geographic factors of the North on adaptive reactions of the human body in terms of pathological physiology and morphology. The aim was to study adaptive reactions of the human body in the north to external factors, which include severe light and cold conditions. Methods. Analysis of current literature on the issue under study. Results. The adaptive rearrangement of the body in the North involves expanding physiological boundaries of individual endocrine and metabolic parameters. Beyond the normal limits of a species, the capacity of body reserve decreases, which may lead to a pathology. Of a great importance are intra-annual fluctuations of hormones associated with the photoperiodism. The rhythmic organization of physiological processes has an adaptive nature as it helps preparing and adapting the body to environmental conditions to maintain its homeostasis. Adaptive changes are known to occur not only at the level of physiological systems but also at the ultrastructural level. Seasonal rhythms affect the structure and function of all systems in the human body. Many pathological processes are associated with development of desynchronosis. Mismatching biorhythms under the action of exogenous or endogenous factors is accompanied by disorders in the original chronostructural organization of physiological functions, which may leads not only to endocrine shifts but also to structural changes in organs. The review addresses the importance of taking into account the features of climatic and geographical factors of the North, which may induce pronounced changes in the structure and function of organs. The above-said is supported by the established imbalance evident as partial hypoplasia of the pancreatic exocrine apparatus associated with a pronounced endocrine component of the gland and stroma. These disorders are considered a prerequisite for development of abnormalities and may underlie congenital pancreatic pathology, such as fibrosis and diabetes. Conclusion. Long-acting stress factors lead to morphological rearrangements of organs and adaptive modifications of their structure.

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Visualizing HIV-1 Capsid and Its Interactions with Antivirals and Host Factors

Viruses ◽

10.3390/v13020246 ◽

2021 ◽

Vol 13 (2) ◽

pp. 246

Author(s):

Morganne Wilbourne ◽

Peijun Zhang

Keyword(s):

Electron Tomography ◽

Host Factors ◽

Viral Infectivity ◽

Hiv Replication ◽

Nuclear Entry ◽

Host Chromosome ◽

X Ray Crystallography ◽

Cryo Electron Microscopy ◽

And Function ◽

Structural Insights

Understanding of the construction and function of the HIV capsid has advanced considerably in the last decade. This is due in large part to the development of more sophisticated structural techniques, particularly cryo-electron microscopy (cryoEM) and cryo-electron tomography (cryoET). The capsid is known to be a pleomorphic fullerene cone comprised of capsid protein monomers arranged into 200–250 hexamers and 12 pentamers. The latter of these induce high curvature necessary to close the cone at both ends. CryoEM/cryoET, NMR, and X-ray crystallography have collectively described these interactions to atomic or near-atomic resolutions. Further, these techniques have helped to clarify the role the HIV capsid plays in several parts of the viral life cycle, from reverse transcription to nuclear entry and integration into the host chromosome. This includes visualizing the capsid bound to host factors. Multiple proteins have been shown to interact with the capsid. Cyclophilin A, nucleoporins, and CPSF6 promote viral infectivity, while MxB and Trim5α diminish the viral infectivity. Finally, structural insights into the intra- and intermolecular interactions that govern capsid function have enabled development of small molecules, peptides, and truncated proteins to disrupt or stabilize the capsid to inhibit HIV replication. The most promising of these, GS6207, is now in clinical trial.

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