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8.A.25 The Ezrin/Radixin/Moesin (Ezrin) Family

Ezrin (cytovillin, villin-2, band 41 homologue, p81; 586 aas) binds to the PDZ domains in EBP50 (NHERF; 8.A.24) which organizes a number of receptors and channels. It contains a FERM domain (residues 200-290) that binds to PDZ domains in many proteins. The binding of ezrin to EBP50 induces major changes in CFTR (3.A.1.202.1) (Li et al., 2005). It provides connections to the cytoskeleton near the plasma membrane. It is a soluble protein that is primarily localized in the cell, for example, to the apical membrane of parietal cells in animals, dependent on other proteins. It is phosphorylated by tyrosine kinases. There are hundreds of homologues in the family including the neurofibromatosis-2 protein, myosin-like proteins and the tegumental antigen. It shows sequence similarity to domains in tyrosine protein-P phosphatases.  There are four 4.1 proteins: 4.1R, 4.1N, 4.1G and 4.1B.  These proteins promote organization of many channel proteins in the cytoplasmic membrane (Baines et al. 2009).

Proteins of the 4.1 family, homologous to ezrin throughout most of their lengths, are characteristic of eumetazoan organisms (Baines et al. 2014). Invertebrates contain single 4.1 genes and the Drosophila model suggests that 4.1 is essential for animal life. Vertebrates have four paralogues, known as 4.1R, 4.1N, 4.1G and 4.1B, which are additionally duplicated in the ray- finned fish. Protein 4.1R was the first to be discovered: it is a major mammalian erythrocyte cytoskeletal protein, essential to the mechanochemical properties of red cell membranes because it promotes the interaction between spectrin and actin in the membrane cytoskeleton. 4.1R also binds certain phospholipids and is required for the stable cell surface accumulation of a number of erythrocyte transmembrane proteins that span multiple functional classes; these include cell adhesion molecules, transporters and a chemokine receptor. The vertebrate 4.1 proteins are expressed in most tissues, and they are required for the correct cell surface accumulation of a very wide variety of membrane proteins including G-Protein coupled receptors, voltage-gated and ligand-gated channels, as well as the classes identified in erythrocytes. Indeed, such large numbers of protein interactions have been mapped for mammalian 4.1 proteins, most especially 4.1R, that it appears that they can act as hubs for membrane protein organization. The range of critical interactions of 4.1 proteins is reflected in disease relationships that include hereditary anaemias, tumour suppression, control of heartbeat and nervous system function. The 4.1 proteins are defined by their domain structure: apart from the spectrin/actin-binding domain they have FERM and FERM-adjacent domains and a unique C-terminal domain. Both the FERM and C-terminal domains can bind transmembrane proteins. The spectrum of interactions of the 4.1 proteins overlaps with that of another membrane-cytoskeleton linker, ankyrin (Baines et al. 2014).

References associated with 8.A.25 family:

Baines, A.J., H.C. Lu, and P.M. Bennett. (2014). The Protein 4.1 family: Hub proteins in animals for organizing membrane proteins. Biochim. Biophys. Acta. 1838: 605-619. 23747363
Baines, A.J., P.M. Bennett, E.W. Carter, and C. Terracciano. (2009). Protein 4.1 and the control of ion channels. Blood Cells Mol Dis 42: 211-215. 19272819
Deng, F., M.G. Price, C.F. Davis, M. Mori, and D.L. Burgess. (2006). Stargazin and other transmembrane AMPA receptor regulating proteins interact with synaptic scaffolding protein MAGI-2 in brain. J. Neurosci. 26: 7875-7884. 16870733
Diaz de Barboza, G., S. Guizzardi, and N. Tolosa de Talamoni. (2015). Molecular aspects of intestinal calcium absorption. World J Gastroenterol 21: 7142-7154. 26109800
Kristó, I., C. Bajusz, B.N. Borsos, T. Pankotai, J. Dopie, F. Jankovics, M.K. Vartiainen, M. Erdélyi, and P. Vilmos. (2017). The actin binding cytoskeletal protein Moesin is involved in nuclear mRNA export. Biochim. Biophys. Acta. 1864: 1589-1604. 28554770
Li, J., Z. Dai, D. Jana, D.J. Callaway, and Z. Bu. (2005). Ezrin controls the macromolecular complexes formed between an adapter protein Na+/H+ exchanger regulatory factor and the cystic fibrosis transmembrane conductance regulator. J Biol Chem. 280: 37634-37643. 16129695
Maitra, S., R.M. Kulikauskas, H. Gavilan, and R.G. Fehon. (2006). The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr. Biol. 16: 702-709. 16581517
McCartney, B.M. and R.G. Fehon. (1996). Distinct cellular and subcellular patterns of expression imply distinct functions for the Drosophila homologues of moesin and the neurofibromatosis 2 tumor suppressor, merlin. J. Cell Biol. 133: 843-852. 8666669
Wu, X., K. Hepner, S. Castelino-Prabhu, D. Do, M.B. Kaye, X.J. Yuan, J. Wood, C. Ross, C.L. Sawyers, and Y.E. Whang. (2000). Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. Proc. Natl. Acad. Sci. USA 97: 4233-4238. 10760291
Yu, J., Y. Zheng, J. Dong, S. Klusza, W.M. Deng, and D. Pan. (2010). Kibra functions as a tumor suppressor protein that regulates Hippo signaling in conjunction with Merlin and Expanded. Dev Cell 18: 288-299. 20159598