Trends in Molecular Medicine
ReviewOrganizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin
Introduction
Plasma membranes of multicellular animals are precisely patterned into well-defined neighborhoods or domains that are optimized for physiological functions, such as vectorial transport of salt and water and electrical signaling. This topographical organization requires mechanisms to prevent diffusion of membrane-spanning proteins in the fluid phospholipid bilayer. In addition, cells must segregate functionally related membrane proteins within the same domains. Spectrins and ankyrins are proteins that are associated with the cytoplasmic surface of the plasma membranes of most metazoan cells. Recent progress demonstrates that these proteins collaborate in both the establishment and maintenance of a surprisingly diverse set of specialized plasma membrane domains. This review summarizes these new insights into the basic cell biology of spectrin and ankyrin and the recently discovered human diseases that occur when these mechanisms fail.
Section snippets
Spectrins and ankyrins
Spectrins are flexible rods 0.2 microns in length with binding sites for F-actin at each end [1] (Figure 1, Figure 2). Spectrins are formed from α and β subunits assembled antiparallel and side-to-side into heterodimers. α/β Heterodimers, in turn, form end-to-end tetramers in which the N-terminus of each α subunit associates with the C-terminus of each β subunit (Figure 1, Figure 2). In human erythrocytes, in which spectrin was first characterized, short actin filaments are each linked to five
Spectrin- and ankyrin-based membrane domains
The lateral membrane domain of epithelial cells is of considerable physiological importance because of its roles in salt and water homeostasis and protection of epithelial tissues from mechanical stress. Moreover, loss of this specialized domain is a hallmark of metastatic cancer cells. Recent studies using RNA interference have revealed that ankyrin-G and β-2 spectrin collaborate in the formation of the lateral membrane of bronchial epithelial cells in addition to their expected function in
Hereditary spherocytosis
Hereditary spherocytosis (HS) is a hemolytic anemia in humans and mice and was the first disease to be linked to spectrin and ankyrin 42, 43, 44. Although mutations of the genes encoding the anion exchanger, band 4.2 (a protein associated with the anion exchanger) and spectrin subunits can all cause spherocytosis, mutations of ankyrin-R (encoded by the ANK1 gene) are responsible for the majority of human cases 45, 46. Mutations in all of these genes result in the same final outcome:
Conclusions and perspectives
Ankyrins and spectrins, first discovered in human erythrocytes, are now known to organize and strengthen the plasma membranes of many types of cell. The basic logic is straightforward: spectrins form a two-dimensional network that is coupled to the inner membrane surface by ankyrins, which in turn bind to diverse membrane-spanning proteins through their ANK repeats. In addition to this scaffolding role, recent advances indicate that ankyrins and spectrins are required for assembly of
Acknowledgements
J.H. is supported by a pre-doctoral grant from the American Heart Association.
References (70)
Rh-RhAG/ankyrin-R, a new interaction site between the membrane bilayer and the red cell skeleton, is impaired by Rh(null)-associated mutation
J. Biol. Chem.
(2003)Purification of an active proteolytic fragment of the membrane attachment site for human erythrocyte spectrin
J. Biol. Chem.
(1978)The ammonium transporter RhBG: requirement of a tyrosine-based signal and ankyrin-G for basolateral targeting and membrane anchorage in polarized kidney epithelial cells
J. Biol. Chem.
(2005)Ankyrin-G is a molecular partner of E-cadherin in epithelial cells and early embryos
J. Biol. Chem.
(2007)- et al.
Lateral membrane biogenesis in human bronchial epithelial cells requires 190-kDa ankyrin-G
J. Biol. Chem.
(2004) Ankyrin-G and beta2-spectrin collaborate in biogenesis of lateral membrane of human bronchial epithelial cells
J. Biol. Chem.
(2007)Dynactin-dependent, dynein-driven vesicle transport in the absence of membrane proteins: a role for spectrin and acidic phospholipids
Mol. Cell
(2001)beta III spectrin binds to the Arp1 subunit of dynactin
J. Biol. Chem.
(2001)- et al.
The ANK repeats of erythrocyte ankyrin form two distinct but cooperative binding sites for the erythrocyte anion exchanger
J. Biol. Chem.
(1995) Morphogenetic roles of classic cadherins
Curr. Opin. Cell Biol.
(1995)
Identification of a conserved ankyrin-binding motif in the family of sodium channel alpha subunits
J. Biol. Chem.
Structural requirements for interaction of sodium channel beta 1 subunits with ankyrin
J. Biol. Chem.
AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier
J. Biol. Chem.
Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment
Cell
AlphaII-spectrin is essential for assembly of the nodes of Ranvier in myelinated axons
Curr. Biol.
Marked reduction of spectrin in hereditary spherocytosis in the common house mouse
Blood
Spectrin deficient inherited hemolytic anemias in the mouse: characterization by spectrin synthesis and mRNA activity in reticulocytes
Cell
Hereditary spherocytosis – defects in proteins that connect the membrane skeleton to the lipid bilayer
Semin. Hematol.
Hematologically important mutations: ankyrin variants in hereditary spherocytosis
Blood Cells Mol. Dis.
Rate of rupture and reattachment of the band 3-ankyrin bridge on the human erythrocyte membrane
J. Biol. Chem.
A novel brain-specific isoform of beta spectrin: isolation and its interaction with Munc13
Biochem. Biophys. Res. Commun.
Presynaptic spectrin is essential for synapse stabilization
Curr. Biol.
A conserved role for Drosophila neuroglian and human L1-CAM in central-synapse formation
Curr. Biol.
Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues
Physiol. Rev.
Visualization of the protein associations in the erythrocyte membrane skeleton
Proc. Natl Acad. Sci. USA
Crystal structure of a 12 ANK repeat stack from human ankyrinR
EMBO J.
Nanospring behaviour of ankyrin repeats
Nature
The ankyrin repeat as molecular architecture for protein recognition
Protein Sci.
DARPins: a true alternative to antibodies
Curr. Opin. Drug Discov. Devel.
A common ankyrin-G-based mechanism retains KCNQ and Nav channels at electrically active domains of the axon
J. Neurosci.
LAD-1, the Caenorhabditis elegans L1CAM homologue, participates in embryonic and gonadal morphogenesis and is a substrate for fibroblast growth factor receptor pathway-dependent phosphotyrosine-based signaling
J. Cell Biol.
Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin
EMBO J.
Modulation of the neuronal glutamate transporter EAAT4 by two interacting proteins
Nature
An SH3 binding region in the epithelial Na+ channel (alpha rENaC) mediates its localization at the apical membrane
EMBO J.
Phosphatidylserine binding sites in erythroid spectrin: location and implications for membrane stability
Biochemistry
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