-
Nature Structural & Molecular Biology Jul 2022The stability and shape of the erythrocyte membrane is provided by the ankyrin-1 complex, but how it tethers the spectrin-actin cytoskeleton to the lipid bilayer and the...
The stability and shape of the erythrocyte membrane is provided by the ankyrin-1 complex, but how it tethers the spectrin-actin cytoskeleton to the lipid bilayer and the nature of its association with the band 3 anion exchanger and the Rhesus glycoproteins remains unknown. Here we present structures of ankyrin-1 complexes purified from human erythrocytes. We reveal the architecture of a core complex of ankyrin-1, the Rhesus proteins RhAG and RhCE, the band 3 anion exchanger, protein 4.2, glycophorin A and glycophorin B. The distinct T-shaped conformation of membrane-bound ankyrin-1 facilitates recognition of RhCE and, unexpectedly, the water channel aquaporin-1. Together, our results uncover the molecular details of ankyrin-1 association with the erythrocyte membrane, and illustrate the mechanism of ankyrin-mediated membrane protein clustering.
Topics: Anion Exchange Protein 1, Erythrocyte; Ankyrins; Cytoskeletal Proteins; Erythrocyte Membrane; Erythrocytes; Humans; Spectrin
PubMed: 35835865
DOI: 10.1038/s41594-022-00792-w -
Current Opinion in Neurobiology Aug 2021Ankyrins are scaffolding proteins widely expressed throughout the nervous system. Ankyrins recruit diverse membrane proteins, including ion channels and cell adhesion... (Review)
Review
Ankyrins are scaffolding proteins widely expressed throughout the nervous system. Ankyrins recruit diverse membrane proteins, including ion channels and cell adhesion molecules, into specialized subcellular membrane domains. These domains are stabilized by ankyrins interacting with the spectrin cytoskeleton. Ankyrin genes are highly associated with a number of neurological disorders, including Alzheimer's disease, schizophrenia, autism spectrum disorders, and bipolar disorder. Here, we discuss ankyrin function and their role in neurological disease. We propose mutations in ankyrins contribute to disease through two primary mechanisms: 1) altered neuronal excitability by disrupting ion channel clustering at key excitable domains, and 2) altered neuronal connectivity via impaired stabilization of membrane proteins.
Topics: Ankyrins; Cell Membrane; Cytoskeleton; Humans; Nervous System Diseases; Spectrin
PubMed: 33485190
DOI: 10.1016/j.conb.2021.01.002 -
Experimental & Molecular Medicine Jul 2022Ankyrin proteins act as molecular scaffolds and play an essential role in regulating cellular functions. Recent evidence has implicated the ANK3 gene, encoding... (Review)
Review
Ankyrin proteins act as molecular scaffolds and play an essential role in regulating cellular functions. Recent evidence has implicated the ANK3 gene, encoding ankyrin-G, in bipolar disorder (BD), schizophrenia (SZ), and autism spectrum disorder (ASD). Within neurons, ankyrin-G plays an important role in localizing proteins to the axon initial segment and nodes of Ranvier or to the dendritic shaft and spines. In this review, we describe the expression patterns of ankyrin-G isoforms, which vary according to the stage of brain development, and consider their functional differences. Furthermore, we discuss how posttranslational modifications of ankyrin-G affect its protein expression, interactions, and subcellular localization. Understanding these mechanisms leads us to elucidate potential pathways of pathogenesis in neurodevelopmental and psychiatric disorders, including BD, SZ, and ASD, which are caused by rare pathogenic mutations or changes in the expression levels of ankyrin-G in the brain.
Topics: Ankyrins; Autism Spectrum Disorder; Bipolar Disorder; Brain; Humans; Neurons
PubMed: 35794211
DOI: 10.1038/s12276-022-00798-w -
Channels (Austin, Tex.) Dec 2022The ankyrin proteins (Ankyrin-R, Ankyrin-B, and Ankyrin-G) are a family of scaffolding, or membrane adaptor proteins necessary for the regulation and targeting of... (Review)
Review
The ankyrin proteins (Ankyrin-R, Ankyrin-B, and Ankyrin-G) are a family of scaffolding, or membrane adaptor proteins necessary for the regulation and targeting of several types of ion channels and membrane transporters throughout the body. These include voltage-gated sodium, potassium, and calcium channels in the nervous system, heart, lungs, and muscle. At these sites, ankyrins recruit ion channels, and other membrane proteins, to specific subcellular domains, which are then stabilized through ankyrin's interaction with the submembranous spectrin-based cytoskeleton. Several recent studies have expanded our understanding of both ankyrin expression and their ion channel binding partners. This review provides an updated overview of ankyrin proteins and their known channel and transporter interactions. We further discuss several potential avenues of future research that would expand our understanding of these important organizational proteins.
Topics: Ankyrins; Cytoskeleton; Ion Channels; Membrane Proteins; Spectrin
PubMed: 36082411
DOI: 10.1080/19336950.2022.2120467 -
Human Molecular Genetics Jul 2023To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics...
ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks.
PURPOSE
To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and homeostatic plasticity in human-induced pluripotent stem cell-derived neurons.
METHODS
We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity.
RESULTS
We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation.
CONCLUSIONS
Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.
Topics: Humans; Axon Initial Segment; Induced Pluripotent Stem Cells; Ankyrins; Neurons; Epilepsy
PubMed: 37195288
DOI: 10.1093/hmg/ddad081 -
Molecules (Basel, Switzerland) Jan 2022Ankyrin is one of the most abundant protein repeat families found across all forms of life. It is found in a variety of multi-domain and single domain proteins in humans...
Ankyrin is one of the most abundant protein repeat families found across all forms of life. It is found in a variety of multi-domain and single domain proteins in humans with diverse number of repeating units. They are observed to occur in several functionally diverse proteins, such as transcriptional initiators, cell cycle regulators, cytoskeletal organizers, ion transporters, signal transducers, developmental regulators, and toxins, and, consequently, defects in ankyrin repeat proteins have been associated with a number of human diseases. In this study, we have classified the human ankyrin proteins into clusters based on the sequence similarity in their ankyrin repeat domains. We analyzed the amino acid compositional bias and consensus ankyrin motif sequence of the clusters to understand the diversity of the human ankyrin proteins. We carried out network-based structural analysis of human ankyrin proteins across different clusters and showed the association of conserved residues with topologically important residues identified by network centrality measures. The analysis of conserved and structurally important residues helps in understanding their role in structural stability and function of these proteins. In this paper, we also discuss the significance of these conserved residues in disease association across the human ankyrin protein clusters.
Topics: Ankyrin Repeat; Ankyrins; Databases, Protein; Humans
PubMed: 35056738
DOI: 10.3390/molecules27020423 -
Life Sciences Mar 2013Since cloning and characterizing the first nociceptive ion channel Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1), other TRP channels involved in nociception... (Review)
Review
Since cloning and characterizing the first nociceptive ion channel Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1), other TRP channels involved in nociception have been cloned and characterized, which include TRP Vanilloid 2 (TRPV2), TRP Vanilloid 3 (TRPV3), TRP Vanilloid 4 (TRPV4), TRP Ankyrin 1 (TRPA1) and TRP Melastatin 8 (TRPM8), more recently TRP Canonical 1, 5, 6 (TRPC1, 5, 6), TRP Melastatin 2 (TRPM2) and TRP Melastatin 3 (TRPM3). These channels are predominantly expressed in C and Aδ nociceptors and transmit noxious thermal, mechanical and chemical sensitivities. TRP channels are modulated by pro-inflammatory mediators, neuropeptides and cytokines. Significant advances have been made targeting these receptors either by antagonists or agonists to treat painful conditions. In this review, we will discuss TRP channels as targets for next generation analgesics and the side effects that may ensue as a result of blocking/activating these receptors, because they are also involved in physiological functions such as release of vasoactive neuropeptides and regulation of vascular tone, maintenance of the body temperature, gastrointestinal motility, urinary bladder control, etc.
Topics: Analgesia; Ankyrins; Humans; Nociceptors; TRPM Cation Channels; TRPV Cation Channels; Transient Receptor Potential Channels
PubMed: 22910182
DOI: 10.1016/j.lfs.2012.08.010 -
Molecular Psychiatry Apr 2023Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder,...
Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A. OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein-protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7A models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7A models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.
Topics: Humans; Mice; Animals; Ankyrins; DNA Copy Number Variations; Epilepsy; Neurons
PubMed: 36604605
DOI: 10.1038/s41380-022-01937-5 -
Molecular and Cellular Neurosciences Sep 2018Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons,... (Review)
Review
Ankyrins are broadly expressed adaptors that organize diverse membrane proteins into specialized domains and link them to the sub-membranous cytoskeleton. In neurons, ankyrins are known to have essential roles in organizing the axon initial segment and nodes of Ranvier. However, recent studies have revealed novel functions for ankyrins at synapses, where they organize and stabilize neurotransmitter receptors, modulate dendritic spine morphology and control adhesion to the presynaptic site. Ankyrin genes have also been highly associated with a range of neurodevelopmental and psychiatric diseases, including bipolar disorder, schizophrenia and autism, which all demonstrate overlap in their genetics, mechanisms and phenotypes. This review discusses the novel synaptic functions of ankyrin proteins in neurons, and places these exciting findings in the context of ANK genes as key neuropsychiatric disorder risk-factors.
Topics: Animals; Ankyrins; Humans; Neurodevelopmental Disorders; Neuronal Plasticity; Synapses
PubMed: 29730177
DOI: 10.1016/j.mcn.2018.04.010 -
Heart Rhythm Dec 2017Over the past decade, ankyrin-B has been identified as a prominent player in cardiac physiology. Ankyrin-B has a multitude of functions, with roles in expression,... (Review)
Review
Over the past decade, ankyrin-B has been identified as a prominent player in cardiac physiology. Ankyrin-B has a multitude of functions, with roles in expression, localization, and regulation of proteins critical for cardiac excitability, cytoskeletal integrity, and signaling. Furthermore, human ANK2 variants that result in ankyrin-B loss of function are associated with "ankyrin-B syndrome," a complex cardiac phenotype that may include bradycardia and heart rate variability, conduction block, atrial fibrillation, QT interval prolongation, and potentially fatal catecholaminergic polymorphic ventricular tachycardia. However, our understanding of the molecular mechanisms underlying ankyrin-B function at baseline and in disease is still not fully developed owing to the complexity of ankyrin-B gene regulation, number of ankyrin-B-associated molecules, multiple roles of ankyrin-B in the heart and other organs that modulate cardiac function, and a host of unexpected clinical phenotypes. In this review, we summarize known roles of ankyrin-B in the heart and the impact of ankyrin-B dysfunction in animal models and in human disease as well as highlight important new findings illustrating the complexity of ankyrin-B signaling.
Topics: Animals; Ankyrins; Cardiovascular Diseases; DNA; DNA Mutational Analysis; Genetic Predisposition to Disease; Humans; Mutation
PubMed: 28765088
DOI: 10.1016/j.hrthm.2017.07.032