Spectrin- and ankyrin-based membrane domains and the evolution of vertebrates

Curr Top Membr. 2013:72:1-37. doi: 10.1016/B978-0-12-417027-8.00001-5.


Spectrin and ankyrin are membrane skeletal proteins that contribute to mechanical support of plasma membranes and micron-scale organization of diverse membrane-spanning proteins. This chapter provides a plausible scenario for the evolution of ankyrin- and spectrin-based membrane domains with a focus on vertebrates. The analysis integrates recent phylogenetic information with functional analyses of spectrin and ankyrin in erythrocytes, axon initial segments and nodes of Ranvier in neurons, T-tubules and intercalated disks of cardiomyocytes, lateral membrane domains of epithelial cells, and costameres of striated muscle. A core spectrin-ankyrin mechanism for coordinating membrane-spanning proteins and mechanically stabilizing membrane bilayers was expanded in vertebrates by gene duplication events, insertion of giant alternately spliced exons of axonal ankyrins, and a versatile peptide-binding fold of ANK repeats that facilitated acquisition of new protein partners. Cell adhesion molecules (CAM), including dystroglycan, L1 CAM family members, and cadherins, are the earliest examples of membrane-spanning proteins with ankyrin-binding motifs and were all present in urochordates. In contrast, ion channels have continued to evolve ankyrin-binding sites in vertebrates. These considerations suggest a model where proto-domains formed through interaction of ankyrin and spectrin with CAMs. These proto-domains then became populated with ion channels that developed ankyrin-binding activity with selective pressure provided by optimization of physiological function. The best example is the axon initial segment where ankyrin-binding activity evolved sequentially and independently first in L1 CAMs, then in voltage-gated sodium channels, and finally in KCNQ2/3 channels, with the selective advantage of fast and precisely regulated signaling.

Keywords: Adaptive evolution; Ankyrin; Axon initial segment; Costamere; Node of Ranvier; Spectrin.

MeSH terms

  • Animals
  • Ankyrins / chemistry
  • Ankyrins / metabolism*
  • Axons / metabolism
  • Biological Evolution*
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism*
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Erythrocytes / cytology
  • Erythrocytes / metabolism
  • Humans
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Spectrin / chemistry
  • Spectrin / metabolism*


  • Ankyrins
  • Spectrin