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Cellular & Molecular Biology Letters 2001An important aspect of the function of the membrane-associated cytoskeleton has been suggested to be to trap and retain selected transmembrane proteins at points on the... (Review)
Review
An important aspect of the function of the membrane-associated cytoskeleton has been suggested to be to trap and retain selected transmembrane proteins at points on the cell surface specified by cell adhesion molecules. In the process, cell adhesion molecules are cross-linked to each other, and so junctional complexes are strengthened. In this short review, we will discuss recent advances in understanding the role of this "accumulation machine" in postsynaptic structures. Function in the brain depends on correct ordering of synaptic intercellular junctions, and in particular the recruitment of receptors and other apparatus of the signalling system to postsynaptic membranes. Spectrin has long been known to be a component of postsynaptic densities, and recent advances in molecular cloning indicate that beta spectrins at PSDs are all "long" C-terminal isoforms characterised by pleckstrin homology domains. Isoforms of protein 4.1 are also present at synapses. All four 4.1 proteins are represented in PSD preparations, but it is 4.1R that is most enriched in PSDs. 4.1R binds to several proteins enriched in PSDs, including the characteristic PSD intermediate filament, alpha-internexin. Both 4.1 and spectrin interact with ionotropic glutamate receptors (AMPA and NMDA receptors, respectively): 4.1 stabilises AMPA receptors on the cell surface. By linking these receptors to the cytoskeletal and cell adhesion molecules that specify glutamatergic synapses, the membrane protein accumulation machine is suggested to direct the formation of postsynaptic signalling complexes.
Topics: Animals; Ankyrins; Brain; Carrier Proteins; Cytoskeletal Proteins; Cytoskeleton; Humans; Intermediate Filament Proteins; Membrane Proteins; Models, Biological; Neuropeptides; Protein Binding; Protein Transport; Receptors, Glutamate; Spectrin; Synapses
PubMed: 11598642
DOI: No ID Found -
PloS One 2015Invadosomes are actin-rich adhesion structures involved in tissue invasion and extracellular matrix (ECM) remodelling. αII-Spectrin, an ubiquitous scaffolding component...
Invadosomes are actin-rich adhesion structures involved in tissue invasion and extracellular matrix (ECM) remodelling. αII-Spectrin, an ubiquitous scaffolding component of the membrane skeleton and a partner of actin regulators (ABI1, VASP and WASL), accumulates highly and specifically in the invadosomes of multiple cell types, such as mouse embryonic fibroblasts (MEFs) expressing SrcY527F, the constitutively active form of Src or activated HMEC-1 endothelial cells. FRAP and live-imaging analysis revealed that αII-spectrin is a highly dynamic component of invadosomes as actin present in the structures core. Knockdown of αII-spectrin expression destabilizes invadosomes and reduces the ability of the remaining invadosomes to digest the ECM and to promote invasion. The ECM degradation defect observed in spectrin-depleted-cells is associated with highly dynamic and unstable invadosome rings. Moreover, FRAP measurement showed the specific involvement of αII-spectrin in the regulation of the mobile/immobile β3-integrin ratio in invadosomes. Our findings suggest that spectrin could regulate invadosome function and maturation by modulating integrin mobility in the membrane, allowing the normal processes of adhesion, invasion and matrix degradation. Altogether, these data highlight a new function for spectrins in the stability of invadosomes and the coupling between actin regulation and ECM degradation.
Topics: Animals; Cell Line; Extracellular Matrix; Gene Knockdown Techniques; Humans; Integrin beta3; Mice; Molecular Imaging; Mutation; Podosomes; Protein Stability; Spectrin
PubMed: 25830635
DOI: 10.1371/journal.pone.0120781 -
Expert Review of Cardiovascular Therapy Jan 2018In the heart, pathways that transduce extracellular environmental cues (e.g. mechanical force, inflammatory stress) into electrical and/or chemical signals at the...
In the heart, pathways that transduce extracellular environmental cues (e.g. mechanical force, inflammatory stress) into electrical and/or chemical signals at the cellular level are critical for the organ-level response to chronic biomechanical/neurohumoral stress. Specifically, a diverse array of membrane-bound receptors and stretch-activated proteins converge on a network of intracellular signaling cascades that control gene expression, protein translation, degradation and/or regulation. These cellular reprogramming events ultimately lead to changes in cell excitability, growth, proliferation, and/or survival. Areas covered: The actin/spectrin cytoskeleton has emerged as having important roles in not only providing structural support for organelle function but also in serving as a signaling 'superhighway,' linking signaling events at/near the membrane to distal cellular domains (e.g. nucleus, mitochondria). Furthermore, recent work suggests that the integrity of the actin/spectrin cytoskeleton is critical for canonical signaling of pathways involved in cellular response to stress. This review discusses these emerging roles for spectrin and consider implications for heart function and disease. Expert commentary: Despite growth in our understanding of the broader roles for spectrins in cardiac myocytes and other metazoan cells, there remain important unanswered questions, the answers to which may point the way to new therapies for human cardiac disease patients.
Topics: Animals; Heart Diseases; Humans; Myocytes, Cardiac; Signal Transduction; Spectrin
PubMed: 29257730
DOI: 10.1080/14779072.2018.1418664 -
Trends in Cell Biology Jan 1998Amid the continual flux of membranes and proteins through the Golgi, the distinctive structure and compartmentalization of the cisternal stacks are preserved.... (Review)
Review
Amid the continual flux of membranes and proteins through the Golgi, the distinctive structure and compartmentalization of the cisternal stacks are preserved. Microtubules and associated motors are required to maintain Golgi structure and for transport to and from the organelle. There is also evidence for Golgi-associated myosins. Recent research has identified a novel Golgi-associated spectrin-based network. In this review, we discuss evidence for this network and the possible roles for spectrin in maintaining Golgi structure and in vesicular transport to and from the Golgi. Overall the link between the cytoskeleton and the Golgi appears to be dynamic in nature, in keeping with the continuous flux of proteins and lipids through this organelle.
Topics: Animals; Cell Line; Cytoskeleton; Golgi Apparatus; Humans; Spectrin
PubMed: 9695804
DOI: 10.1016/s0962-8924(97)01195-1 -
Proceedings of the National Academy of... Jun 2020Proteins synthesized in the cell can begin to fold during translation before the entire polypeptide has been produced, which may be particularly relevant to the folding...
Proteins synthesized in the cell can begin to fold during translation before the entire polypeptide has been produced, which may be particularly relevant to the folding of multidomain proteins. Here, we study the cotranslational folding of adjacent domains from the cytoskeletal protein α-spectrin using force profile analysis (FPA). Specifically, we investigate how the cotranslational folding behavior of the R15 and R16 domains are affected by their neighboring R14 and R16, and R15 and R17 domains, respectively. Our results show that the domains impact each other's folding in distinct ways that may be important for the efficient assembly of α-spectrin, and may reduce its dependence on chaperones. Furthermore, we directly relate the experimentally observed yield of full-length protein in the FPA assay to the force exerted by the folding protein in piconewtons. By combining pulse-chase experiments to measure the rate at which the arrested protein is converted into full-length protein with a Bell model of force-induced rupture, we estimate that the R16 domain exerts a maximal force on the nascent chain of ∼15 pN during cotranslational folding.
Topics: Escherichia coli; Molecular Dynamics Simulation; Protein Biosynthesis; Protein Domains; Protein Folding; Spectrin
PubMed: 32513720
DOI: 10.1073/pnas.1909683117 -
ELife Apr 2020Axons span extreme distances and are subject to significant stretch deformations during limb movements or sudden head movements, especially during impacts. Yet, axon...
Axons span extreme distances and are subject to significant stretch deformations during limb movements or sudden head movements, especially during impacts. Yet, axon biomechanics, and its relation to the ultrastructure that allows axons to withstand mechanical stress, is poorly understood. Using a custom developed force apparatus, we demonstrate that chick dorsal root ganglion axons exhibit a tension buffering or strain-softening response, where its steady state elastic modulus decreases with increasing strain. We then explore the contributions from the various cytoskeletal components of the axon to show that the recently discovered membrane-associated actin-spectrin scaffold plays a prominent mechanical role. Finally, using a theoretical model, we argue that the actin-spectrin skeleton acts as an axonal tension buffer by reversibly unfolding repeat domains of the spectrin tetramers to release excess mechanical stress. Our results revise the current viewpoint that microtubules and their associated proteins are the only significant load-bearing elements in axons.
Topics: Actins; Animals; Axons; Biomechanical Phenomena; Cells, Cultured; Chickens; Microtubules; Protein Folding; Spectrin; Stress, Mechanical
PubMed: 32267230
DOI: 10.7554/eLife.51772 -
Translational Research : the Journal of... May 2022Spectrin, as one of the major components of a plasma membrane-associated cytoskeleton, is a cytoskeletal protein composed of the modular structure of α and β subunits.... (Review)
Review
Spectrin, as one of the major components of a plasma membrane-associated cytoskeleton, is a cytoskeletal protein composed of the modular structure of α and β subunits. The spectrin-based skeleton is essential for preserving the integrity and mechanical characteristics of the cell membrane. Moreover, spectrin regulates a variety of cell processes including cell apoptosis, cell adhesion, cell spreading, and cell cycle. Dysfunction of spectrins is implicated in various human diseases including hemolytic anemia, neurodegenerative diseases, ataxia, heart diseases, and cancers. Here, we briefly discuss spectrins function as well as the clinical manifestations and currently known molecular mechanisms of human diseases related to spectrins, highlighting that strategies for targeting regulation of spectrins function may provide new avenues for therapeutic intervention for these diseases.
Topics: Cell Adhesion; Cell Cycle; Cell Membrane; Humans; Spectrin
PubMed: 34979321
DOI: 10.1016/j.trsl.2021.12.009 -
Hearing Research Sep 2022Reports have proposed a putative role for βV spectrin in outer hair cells (OHCs) of the cochlea. In an ongoing investigation of the role of the cytoskeleton in...
Reports have proposed a putative role for βV spectrin in outer hair cells (OHCs) of the cochlea. In an ongoing investigation of the role of the cytoskeleton in electromotility, we tested mice with a targeted exon deletion of βV spectrin (Spnb5), and unexpectedly find that Spnb5 animals' auditory thresholds are unaffected. Similarly, these mice have normal OHC electromechanical activity (otoacoustic emissions) and non-linear capacitance. In contrast, magnitudes of auditory brainstem response (ABR) wave 1-amplitudes are significantly reduced. Evidence of a synaptopathy was absent with normal hair cell CtBP2 counts. In Spnb5 mice, the number of afferent and efferent nerve fibers is decreased. Consistent with this data, Spnb5 mRNA is present in Type I and II spiral ganglion neurons, but undetectable in OHCs. Together, these data establish that βV spectrin is important for hearing, affecting neuronal structure and function. Significantly, these data support that βV spectrin as is not functionally important to OHCs as has been previously suggested.
Topics: Animals; Cochlea; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory, Outer; Mice; Mice, Knockout; Otoacoustic Emissions, Spontaneous; Spectrin
PubMed: 35864018
DOI: 10.1016/j.heares.2022.108564 -
Seminars in Hematology Jan 1993
Review
Topics: Amino Acid Sequence; Base Sequence; Erythrocyte Membrane; Hematologic Diseases; Humans; Molecular Sequence Data; Mutation; Polymorphism, Restriction Fragment Length; Spectrin
PubMed: 8094577
DOI: No ID Found -
The Journal of Neuroscience : the... Nov 2017Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments...
Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse β subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and superresolution microscopy, we show that αII and βIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated mice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all β spectrins. αII spectrin-deficient mice die before 1 month of age and have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system. Spectrin cytoskeletons play diverse roles in neurons, including assembly of excitable domains such as the axon initial segment (AIS) and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show that αII spectrin partners with βIV spectrin to form a periodic cytoskeleton at the AIS. Using a new αII spectrin conditional knock-out mouse, we show that αII spectrin is required for AIS assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology.
Topics: Action Potentials; Animals; Axons; COS Cells; Cells, Cultured; Chlorocebus aethiops; Cytoskeleton; Gene Deletion; Hippocampus; Mice; Mice, Inbred C57BL; Ranvier's Nodes; Spectrin
PubMed: 29038240
DOI: 10.1523/JNEUROSCI.2112-17.2017