Review
Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin

https://doi.org/10.1016/j.molmed.2007.11.005Get rights and content

Ankyrin and spectrin were first discovered as binding partners in the membrane skeleton of human erythrocytes. Mutations in genes encoding these proteins cause hereditary spherocytosis. Recent advances reveal that ankyrin and spectrin are required for organization of a surprisingly diverse set of proteins, including ion channels and cell adhesion molecules that are localized in specialized membrane domains in many cell types. New insights into the cell biology of ankyrin and spectrin reveal that these proteins actively participate in assembly of specialized membrane domains in addition to their conventional maintenance role as scaffolding proteins. Recently described inherited human diseases due to defects in spectrin or ankyrin include spinocerebellar ataxia type 5 and a cardiac arrhythmia, termed sick sinus syndrome with bradycardia or ankyrin-B syndrome. Together, these studies identify an emerging paradigm for pathogenesis of human disease where failure in cellular localization of membrane-spanning proteins results in loss of physiological function.

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.

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