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:
The 4.1R protein of 864 aas. Interacts with many membrane transporters, adhesins and receptors as well as cytoskelectal proteins to help organize the cell envelope (Baines et al. 2014). For example, it interacts with the PMCA1b ATPase (TC# 3.A.3.2.25) (Diaz de Barboza et al. 2015).
Animals
The 4.1R protein of Homo sapiens
Merlin, Mer, EMR2, of 635 aas and 1 TMS. Mer acts synergistically along with Ex and Kibra to regulate the Hippo signaling pathway (Yu et al. 2010). Merlin and Expanded (Q07436; 1,427 aas) function synergistically to control proliferation by regulating the abundance, localization, and turnover of cell-surface receptors (Maitra et al. 2006).
Merlin of Drosophila melanogaster (Fruit fly)
Moesin, Moe, EMR1 of 578 aas and 1 TMS. Moesin is involved in connections of major cytoskeletal structures to the plasma membrane (McCartney and Fehon 1996). It plays a role in nuclear mRNA export together with the mRNA export factor PCID2 (Q9VTL1; 395 aas) and other messenger ribonucleoprotein (mRNP) particles (Kristó et al. 2017).
Moesin of Drosophila melanogaster (Fruit fly)