scholarly journals Molecular basis of F-actin regulation and sarcomere assembly via myotilin

2020 ◽  
Author(s):  
Julius Kostan ◽  
Miha Pavšič ◽  
Vid Puž ◽  
Thomas C. Schwarz ◽  
Friedel Drepper ◽  
...  
Keyword(s):  
Structural Model ◽  
Structural Integrity ◽  
Striated Muscle ◽  
Actin Binding ◽  
List Type ◽  
Striated Muscles ◽  
Conformational Ensembles ◽  
Sarcomere Assembly ◽  
Flanking Regions

AbstractSarcomeres, the basic contractile units of striated muscle cells, contain arrays of thin (actin) and thick (myosin) filaments that slide past each other during contraction. The Ig-like domain containing protein myotilin provides structural integrity to Z-discs - the boundaries between adjacent sarcomeres. Myotilin binds to Z-disc components, including F-actin and α-actinin-2, but the molecular mechanism of binding and implications of these interactions on Z-disc integrity are still elusive. We used a combination of small angle X-ray scattering, cross-linking mass spectrometry, biochemical and molecular biophysics approaches. We discovered that myotilin displays conformational ensembles in solution. We generated a structural model of the F-actin:myotilin complex that revealed how myotilin interacts with and stabilizes F-actin via its Ig-like domains and flanking regions. Mutant myotilin designed with impaired F-actin binding showed increased dynamics in cells. Structural analyses and competition assays uncovered that myotilin displaces tropomyosin from F-actin. Our findings suggest a novel role of myotilin as a co-organizer of Z-disc assembly and advance our mechanistic understanding of myotilin’s structural role in Z-discs.Significance StatementSarcomeres are the primary structural and functional unit of striated muscles, conferring movement in all animals. The Z-disk is the boundary between adjacent sarcomeres, where actin filaments (F-actin) are anchored. Z-disc protein myotilin, is a scaffold protein, which provides structural integrity to the Z-disc by multiple interactions to its central components, including F-actin and α-actinin-2. Here we provide the structure of myotilin, revealing its structural plasticity in solution and the first integrative structural model of its complex with F-actin. We further show that myotilin displaces tropomyosin from F-actin, implying a novel role of myotilin in sarcomere biogenesis beyond being an interaction hub for Z-disk partners.Highlights፧Myotilin is structurally described as a dynamic ensemble፧Flanking regions enhance F-acting binding to tandem Ig domains፧Integrative structural model of myotilin bound to F-actin፧Myotilin displaces tropomyosin from F-actin, suggesting an organisational role in Z-disc

scholarly journals Molecular basis of F-actin regulation and sarcomere assembly via myotilin

PLoS Biology ◽  
2021 ◽  
Vol 19 (4) ◽  
pp. e3001148
Author(s):  
Julius Kostan ◽  
Miha Pavšič ◽  
Vid Puž ◽  
Thomas C. Schwarz ◽  
Friedel Drepper ◽  
...  
Keyword(s):  
Structural Model ◽  
Structural Integrity ◽  
Striated Muscle ◽  
Actin Binding ◽  
Conformational Ensembles ◽  
X Ray Scattering ◽  
Sarcomere Assembly ◽  
Flanking Regions ◽  
Competition Assays

Sarcomeres, the basic contractile units of striated muscle cells, contain arrays of thin (actin) and thick (myosin) filaments that slide past each other during contraction. The Ig-like domain-containing protein myotilin provides structural integrity to Z-discs—the boundaries between adjacent sarcomeres. Myotilin binds to Z-disc components, including F-actin and α-actinin-2, but the molecular mechanism of binding and implications of these interactions on Z-disc integrity are still elusive. To illuminate them, we used a combination of small-angle X-ray scattering, cross-linking mass spectrometry, and biochemical and molecular biophysics approaches. We discovered that myotilin displays conformational ensembles in solution. We generated a structural model of the F-actin:myotilin complex that revealed how myotilin interacts with and stabilizes F-actin via its Ig-like domains and flanking regions. Mutant myotilin designed with impaired F-actin binding showed increased dynamics in cells. Structural analyses and competition assays uncovered that myotilin displaces tropomyosin from F-actin. Our findings suggest a novel role of myotilin as a co-organizer of Z-disc assembly and advance our mechanistic understanding of myotilin’s structural role in Z-discs.

scholarly journals Identification of Xin-repeat proteins as novel ligands of the SH3 domains of nebulin and nebulette and analysis of their interaction during myofibril formation and remodeling

2013 ◽  
Vol 24 (20) ◽  
pp. 3215-3226 ◽  
Author(s):  
Stefan Eulitz ◽  
Florian Sauer ◽  
Marie-Cecile Pelissier ◽  
Prisca Boisguerin ◽  
Sibylle Molt ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Muscle Cells ◽  
Sh3 Domain ◽  
Bimolecular Fluorescence Complementation ◽  
Actin Binding ◽  
Binding Motifs ◽  
Sh3 Domains ◽  
Repeat Proteins ◽  
Attachment Sites

The Xin actin-binding repeat–containing proteins Xin and XIRP2 are exclusively expressed in striated muscle cells, where they are believed to play an important role in development. In adult muscle, both proteins are concentrated at attachment sites of myofibrils to the membrane. In contrast, during development they are localized to immature myofibrils together with their binding partner, filamin C, indicating an involvement of both proteins in myofibril assembly. We identify the SH3 domains of nebulin and nebulette as novel ligands of proline-rich regions of Xin and XIRP2. Precise binding motifs are mapped and shown to bind both SH3 domains with micromolar affinity. Cocrystallization of the nebulette SH3 domain with the interacting XIRP2 peptide PPPTLPKPKLPKH reveals selective interactions that conform to class II SH3 domain–binding peptides. Bimolecular fluorescence complementation experiments in cultured muscle cells indicate a temporally restricted interaction of Xin-repeat proteins with nebulin/nebulette during early stages of myofibril development that is lost upon further maturation. In mature myofibrils, this interaction is limited to longitudinally oriented structures associated with myofibril development and remodeling. These data provide new insights into the role of Xin actin-binding repeat–containing proteins (together with their interaction partners) in myofibril assembly and after muscle damage.

Titin: central player of hypertrophic signaling and sarcomeric protein quality control

2014 ◽  
Vol 395 (11) ◽  
pp. 1341-1352 ◽  
Author(s):  
Sebastian Kötter ◽  
Christian Andresen ◽  
Martina Krüger
Keyword(s):  
Quality Control ◽  
Protein Turnover ◽  
Protein Quality ◽  
Striated Muscle ◽  
Muscle Cells ◽  
Central Position ◽  
Sarcomeric Protein ◽  
Hypertrophic Signaling ◽  
Sarcomere Assembly

Abstract The giant sarcomeric protein titin has multiple important functions in striated muscle cells. Due to its gigantic size, its central position in the sarcomere and its elastic I-band domains, titin is a scaffold protein that is important for sarcomere assembly, and serves as a molecular spring that defines myofilament distensibility. This review focuses on the emerging role of titin in mechanosensing and hypertrophic signaling, and further highlights recent evidence that links titin to sarcomeric protein turnover.

scholarly journals Antibodies to striated muscle and acetylcholine receptors in evaluation of surgical treatment outcomes in patients with autoimmune myasthenia gravis

2017 ◽  
Vol 176 (3) ◽  
pp. 21-27
Author(s):  
M. G. Tovbina ◽  
V. G. Pishchik ◽  
S. V. Lapin ◽  
S. M. Nuraliev
Keyword(s):  
Surgical Treatment ◽  
Myasthenia Gravis ◽  
Treatment Outcomes ◽  
Antibody Titer ◽  
Acetylcholine Receptors ◽  
Striated Muscle ◽  
Striated Muscles ◽  
Course Material ◽  
Autoimmune Myasthenia

OBJECTIVE. The authors evaluated the role of antibodies to striated muscle and acetylcholine receptors in diagnostics of myasthenia gravis and thymoma, as well as outcomes of thymectomy and prognosis of myasthenia course. MATERIAL AND METHODS. The study investigated correlations of antibody content to striated muscles and acetylcholine receptors from the presence and size of thymoma, myasthenia in 157 patients with various pathologies of the thymus. The dynamics of antibody concentrations was followed up after thymectomy. RESULTS. Antibody titer to striated muscle depended on the presence and size of thymoma, severity of myasthenia and changed after thymectomy. Concentration of antibodies was associated with the presence of thymoma and it didn’t change after surgical treatment. Thymoma wasn’t revealed in patients who were seronegative to both antibodies. CONCLUSIONS. Seropositivity according to one of antibody could indicate the presence of thymoma, but its absence to both antibodies allowed doctors to eliminate this diagnosis. Antibodies to acetylcholine receptors are important markers of myasthenia. Monitoring of antibody titer dynamics to striated muscles after thymectomy could be useful for assessment of response to surgical treatment and prognosis of course of myasthenia.

scholarly journals The emerging role of physical modeling in the future of structure determination

2017 ◽  
Author(s):  
Kari Gaalswyk ◽  
Mir Ishruna Muniyat ◽  
Justin L. MacCallum
Keyword(s):  
Structure Determination ◽  
Physical Modeling ◽  
Physical Models ◽  
List Type ◽  
Biomolecular Structure ◽  
Conformational Ensembles ◽  
Making Sense ◽  
Physical Insight ◽  
Ambiguous Data

AbstractBiomolecular structure determination has long relied on heuristics based on physical insight; however, recent efforts to model conformational ensembles and to make sense of sparse, ambiguous, and noisy data have revealed the value of detailed, quantitative physical models in structure determination. We review these two key challenges, describe different approaches to physical modeling in structure determination, and illustrate several successes and emerging technologies enabled by physical modeling.HighlightsQuantitative physical modeling is emerging as a key tool in structure determinationThere are different approaches to incorporate physical modeling into structure determinationModeling conformational ensembles and making sense of sparse, noisy, and ambiguous data are two challenges where physical modeling can play a prominent role

scholarly journals Potential Role of Drebrin A, an F-Actin Binding Protein, in Reactive Synaptic Plasticity after Pilocarpine-Induced Seizures: Functional Implications in Epilepsy

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Lotfi Ferhat
Keyword(s):  
Structural Integrity ◽  
Synapse Formation ◽  
Specific Binding ◽  
Treatment Options ◽  
Critical Role ◽  
Synaptic Function ◽  
Actin Binding ◽  
Spine Density ◽  
Developmentally Regulated

Several neurological disorders characterized by cognitive deficits, including Alzheimer's disease, down syndrome, and epilepsy exhibit abnormal spine density and/or morphology. Actin-based cytoskeleton network dynamics is critical for the regulation of spine morphology and synaptic function. In this paper, I consider the functions of drebrin A in cell shaping, spine plasticity, and synaptic function. Developmentally regulated brain protein (drebrin A) is one of the most abundant neuron-specific binding proteins of F-actin and its expression is increased in parallel with synapse formation. Drebrin A is particularly concentrated in dendritic spines receiving excitatory inputs. Our recent findings point to a critical role of DA in dendritic spine structural integrity and stabilization, likely via regulation of actin cytoskeleton dynamics, and glutamatergic synaptic function that underlies the development of spontaneous recurrent seizures in pilocarpine-treated animals. Further research into this area may provide useful insights into the pathology of status epilepticus and epileptogenic mechanisms and ultimately may provide the basis for future treatment options.

Distribution of c-protein isoforms in sarcomeres of developing chick skeletal muscle

1988 ◽  
Vol 46 ◽  
pp. 226-227
Author(s):  
D. A. Fischman ◽  
J. E. Dennis ◽  
T. Obinata ◽  
H. Takano-Ohmuro
Keyword(s):  
Skeletal Muscles ◽  
Thick Filament ◽  
Protein Isoforms ◽  
Actin Binding ◽  
Striated Muscles ◽  
C Protein ◽  
Sarcomeric Protein ◽  
Thick Filaments ◽  
Cross Bridges ◽  
Bridge Bearing

C-protein is a 150 kDa protein found within the A bands of all vertebrate cross-striated muscles. By immunoelectron microscopy, it has been demonstrated that C-protein is distributed along a series of 7-9 transverse stripes in the medial, cross-bridge bearing zone of each A band. This zone is now termed the C-zone of the sarcomere. Interest in this protein has been sparked by its striking distribution in the sarcomere: the transverse repeat between C-protein stripes is 43 nm, almost exactly 3 times the 14.3 nm axial repeat of myosin cross-bridges along the thick filaments. The precise packing of C-protein in the thick filament is still unknown. It is the only sarcomeric protein which binds to both myosin and actin, and the actin-binding is Ca-sensitive. In cardiac and slow, but not fast, skeletal muscles C-protein is phosphorylated. Amino acid composition suggests a protein of little or no αhelical content. Variant forms (isoforms) of C-protein have been identified in cardiac, slow and embryonic muscles.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

scholarly journals Early oxygen levels contribute to brain injury in extremely preterm infants

2021 ◽  
Author(s):  
Krista Rantakari ◽  
Olli-Pekka Rinta-Koski ◽  
Marjo Metsäranta ◽  
Jaakko Hollmén ◽  
Simo Särkkä ◽  
...  
Keyword(s):  
Preterm Infants ◽  
Brain Structures ◽  
High Oxygen ◽  
List Type ◽  
Neurodevelopmental Outcomes ◽  
Oxygen Levels ◽  
Arterial Blood ◽  
Extremely Preterm ◽  
Extremely Preterm Infants

Abstract Background Extremely low gestational age newborns (ELGANs) are at risk of neurodevelopmental impairments that may originate in early NICU care. We hypothesized that early oxygen saturations (SpO2), arterial pO2 levels, and supplemental oxygen (FiO2) would associate with later neuroanatomic changes. Methods SpO2, arterial blood gases, and FiO2 from 73 ELGANs (GA 26.4 ± 1.2; BW 867 ± 179 g) during the first 3 postnatal days were correlated with later white matter injury (WM, MRI, n = 69), secondary cortical somatosensory processing in magnetoencephalography (MEG-SII, n = 39), Hempel neurological examination (n = 66), and developmental quotients of Griffiths Mental Developmental Scales (GMDS, n = 58). Results The ELGANs with later WM abnormalities exhibited lower SpO2 and pO2 levels, and higher FiO2 need during the first 3 days than those with normal WM. They also had higher pCO2 values. The infants with abnormal MEG-SII showed opposite findings, i.e., displayed higher SpO2 and pO2 levels and lower FiO2 need, than those with better outcomes. Severe WM changes and abnormal MEG-SII were correlated with adverse neurodevelopment. Conclusions Low oxygen levels and high FiO2 need during the NICU care associate with WM abnormalities, whereas higher oxygen levels correlate with abnormal MEG-SII. The results may indicate certain brain structures being more vulnerable to hypoxia and others to hyperoxia, thus emphasizing the role of strict saturation targets. Impact This study indicates that both abnormally low and high oxygen levels during early NICU care are harmful for later neurodevelopmental outcomes in preterm neonates. Specific brain structures seem to be vulnerable to low and others to high oxygen levels. The findings may have clinical implications as oxygen is one of the most common therapies given in NICUs. The results emphasize the role of strict saturation targets during the early postnatal period in preterm infants.

scholarly journals 332 The diagnostic role of shunt series radiographs (SSR) in children presenting to the children’s emergency department (CED) with suspected ventriculoperitoneal (VP) shunt failure

2020 ◽  
Vol 37 (12) ◽  
pp. 852.3-853
Author(s):  
Angharad Griffiths ◽  
Ikechukwu Okafor ◽  
Thomas Beattie
Keyword(s):  
Clinical Outcome ◽  
Sensitivity And Specificity ◽  
Clinical Information ◽  
Flow Diagram ◽  
List Type ◽  
Shunt Failure ◽  
Vp Shunt ◽  
Wide Range ◽  
Diagnostic Role

Aims/Objectives/BackgroundVP shunts are used to drain CSF from the cranial vault because of a wide range of pathologies and, like any piece of hardware, can fail. Traditionally investigations include SSR and CT. This project examines the role of SSR in evaluating children with suspected VP shunt failure.Primary outcome: Sensitivity and specificity of SSR in children presenting to the CED with concern for shunt failure.Methods/DesignConducted in a single centre, tertiary CED of the national Irish Neurosurgical(NS) referral centre (ED attendance:>50,000 patients/year). 100 sequential SSR requested by the CED were reviewed. Clinical information was extracted from electronic requests. Shunt failure was defined by the need for NS intervention(Revision).Abstract 332 Figure 1Abstract 332 Figure 2Results/ConclusionsSensitivity and specificity is presented in figure 1 (two by two table).100 radiographs performed in 84 children.22% shunts revised (see flow diagram).7 SSR’s were abnormal.85% (n=6) shunts revised. [5 following abnormal CT].Of the normal SSR’s; 16 had abnormal CT and revised.85/100 received CT.64 of 85 CT’s (75%) were normal.□6 of the 64 had focal shunt concern.SSR’s shouldn’t be used in isolation. NPV&PPV, Sensitivity&Specificity is low.SSR’s are beneficial where there’s concern over focal shunt problems (injury/pain/swelling) or following abnormal CT.VP shunt failure is not well investigated with SSR alone.SSR’s could be omitted where there is no focal shunt concern/after normal CT (without impacting clinical outcome) reducing radiation exposure and reduce impact on CED’s.59 SSR’s could have been avoided without adverse clinical outcome.

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