Mammalian αI-spectrin is a neofunctionalized polypeptide adapted to small highly deformable erythrocytes

^*Red Cell Physiology Laboratory, New York Blood Center, New York, NY 10021; ^†King's College London, Randall Division of Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, London SE1 1UL, United Kingdom; and ^‡Department of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, United Kingdom

Edited by Daniel Branton, Harvard University, Cambridge, MA, and approved November 21, 2005 (received for review September 6, 2005)

Abstract

Mammalian red blood cells, unlike those of other vertebrates, must withstand the rigors of circulation in the absence of new protein synthesis. Key to this is plasma membrane elasticity deriving from the protein spectrin, which forms a network on the cytoplasmic face. Spectrin is a tetramer (αβ)₂, made up of αβ dimers linked head to head. We show here that one component of erythrocyte spectrin, αI, is encoded by a gene unique to mammals. Phylogenetic analysis suggests that the other α-spectrin gene (αII) common to all vertebrates was duplicated after the emergence of amphibia, and that the resulting αI gene was preserved only in mammals. The activities of αI and αII spectrins differ in the context of the human red cell membrane. An αI-spectrin fragment containing the site of head-to-head interaction with the β-chain binds more weakly than the corresponding αII fragment to this site. The latter competes so strongly with endogenous αI as to cause destabilization of membranes at 100-fold lower concentration than the αI fragment. The efficacies of αI/αII chimeras indicate that the partial structural repeat, which binds to the complementaryβ-spectrin element, and the adjacent complete repeat together determine the strength of the dimer–dimer interaction on the membrane. Alignment of all available α-spectrin N-terminal sequences reveals three blocks of sequence unique to αI. Furthermore, human αII-spectrin is closer to fruitfly α-spectrin than to human αI-spectrin, consistent with adaptation of αI to new functions. We conclude that αI-spectrin represents a neofunctionalized spectrin adapted to the rapid make and break of tetramers.

Footnotes

↵ § To whom correspondence should be addressed. E-mail: a.j.baines{at}kent.ac.uk.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.