New insights into potential functions for the protein 4.1superfamily of proteins in kidney epithelium Page: 2 of 32
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Protein 4.1 in kidney physio-pathology
In this review, we present evidence for potential interactions of the three major kidney protein 4.1 gene products with
selected binding partners in an attempt to delineate the functions that these cytoskeletal proteins may play in kidney and in other
epithelia. The potential functional relevance of protein 4.1 interactions with beta amyloid precursor protein (beta-APP), members
of the 14-3-3 family of proteins, and the cell-swelling activated chloride channel pICln, will be explored. The involvement of
another member of the protein 4.1 superfamily, ezrin, in kidney structure, function and pathology is also discussed in detail.
Renal ankyrins will be evoked briefly since they are described in another chapter of this issue (see Mohler and Bennett).
3. PROTEIN 4.1 STRUCTURE
Protein 4.1 belongs to the Ezrin/Radixin/Moesin (ERM) superfamily of adapter proteins that bridge membrane proteins
and actin filaments (4, 54). Members of the ERM family share a homologous region, referred to as the FERM
(Four. 1/Ezrin/Radixin/Moesin) domain (55), suggesting that they may associate with identical or related membrane proteins. The
family of 4.1 proteins is composed of prototypical red blood cell 4.1R (56-59), and three homologs, 4.1G (60, 61), 4.1N (62-65)
and 4.1B (66-69). Protein 4.1 genes differ in their expression pattern: 4.iR is predominantly expressed in hematopoietic tissues,
and in regions of brain and kidney (66, 70, 71); 4.1G shows a broad distribution (60, 61, 70) but, unlike the three other 4.1
proteins, it is not expressed in kidney (71, 72); 4. iN is mostly neuron- and kidney- specific with low expression in the retina and
gastro-intestinal epithelium (62, 71); and 4.1B is present in regions of brain, thymus, liver, gastro-intestinal tract, pancreas,
kidney, and testis (53, 66, 71-75). The four protein 4.1 genes have been mapped on both man and mouse chromosomes (66, 69).
They share a similar organization characterized by the existence of multiple initiation sites combined with a large number of
alternative exons. This results in the generation of a broad repertoire of isoforms from each protein 4.1 gene (30, 34, 58, 59, 71,
Well-defined structural domains have been delineated within the protein 4.1 coding region (Figure 1) (94). As
illustrated in Figure 2, the 30kD FERM domain, also referred to as MBD domain, mediates interaction of 4.iR and/or its
homologs with numerous binding partners including various transmembrane proteins such as the anion exchanger AE1 (or band
3) (95-97), glycophorin C (25, 98-105), CD44 (23), nectin (106) and Neurexins such as Paranodin (107-110), PDZ domain-
containing proteins p55 (12, 19, 111), discs large (Dlg) protein, also referred to as synapse-associated protein 97 (SAP97) (31,
112, 113), and CASK (29, 114), cytoskeletal protein tubulin (115, 116), a swelling-activated chloride channel (46), and signaling
molecules including 14-3-3 proteins (50, 117) and calmodulin (111). The FERM domain also mediates interaction of 4.iR with
phosphatidylserine (118) and, by analogy with other members of the ERM superfamily, likely with phosphatidylinositol 4,5-
bisphosphate (PIP2) (119). Importantly, several studies have established that interactions of ERM proteins with PIP2 play a key
role in their proper membrane targeting (120, 121). The mapping of most of the interactions described above and the
crystallization of 4.iR FERM domain (122, 123) has unveiled the complex structure of protein scaffolds organized around this
key functional domain. A 10kD domain, which mediates 4.iR interaction with spectrin and actin, is referred to as spectrin-actin
binding (SAB) domain (16, 124-129). Unlike 4.1R, 4.1G and 4.1B, 4.lN is unable to form a ternary complex with spectrin and
actin due to the poor conservation of its SAB domain (130). The SAB domain harbors also a nuclear localization signal (35, 131)
whose activity is modulated by the FERM domain and the unique region U1 (34, 35, 132-134). The 22-24kD C-terminal domain
(CTD) interacts with various proteins including receptors (13, 14, 17, 18, 20, 26, 27), tight junction proteins (135) and the nuclear
mitotic apparatus-associated protein NuMA (36, 42). The four protein 4.1 genes show high homology in their FERM, SAB
(except for 4.iN), and CTD domains (Figure 1), suggesting that they may share common functions.
In contrast, the unique regions Ul, U2 and U3, interspersed between the conserved domains, may confer specific
regulatory functions upon each 4.1 protein (Figure 1). The unique region U1 has been shown to modulate 4.1R nuclear
translocation (34, 35, 134). This region also interacts with calmodulin in a calcium-dependent manner (136) and with a
centrosomal-associated protein (38). The unique region Ul also harbors a phosphorylation site for the cyclin-dependent cdc2
kinase (37), the level of phosphorylation of 4.iR varying during the cell cycle. No binding partners for the U2 and U3 unique
regions have been identified so far. The unique region U2 contains a key Ser residue that is the primary substrate for protein
kinase C (PKC)-dependent phosphorylation of 4.1R (137). Importantly, phosphorylation of this Ser residue leads to a decrease in
4.iR interaction with transmembrane protein glycophorin C and with spectrin and actin. Given the conservation of this Ser
residue and of the surrounding amino acids in all four 4.1 proteins (Figure 3), one may anticipate that PKC-dependent
phosphorylation will play a key role in regulation of 4.1G, 4. iN and 4.1B function as well. Importantly, the U2 region has been
recently shown to confer upon 4.1B its anti-proliferative properties through a still unknown mechanism (51). No function has
been assigned to the U3 region yet. Of particular note, inclusion or exclusion of this alternative U3 region is a hallmark of
epithelial 4.iR and 4.iN, respectively (30, 71). This intriguing feature likely reflects unique properties assigned to each of these
protein 4.1 gene products in epithelia, including kidney. The emerging concept is that the unique regions act as modulators of
protein 4.1 interactions mediated by the conserved domains and that tissue- and cell-specific splicing patterns in those regions
confer upon each protein isoform unique characteristics.
4. CYTOSKELETON AND KIDNEY ARCHITECTURE AND FUNCTION
The nephron is composed of a monolayer of highly polarized epithelial cells that are uniquely suited to perform specific
transport functions. The nonrandom distribution of membrane proteins reflects the vectorial transport functions performed by
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Calinisan, Venice; Gravem, Dana; Chen, Ray Ping-Hsu; Brittin,Sachi; Mohandas, Narla; Lecomte, Marie-Christine et al. New insights into potential functions for the protein 4.1superfamily of proteins in kidney epithelium, article, June 17, 2005; Berkeley, California. (digital.library.unt.edu/ark:/67531/metadc892527/m1/2/: accessed October 23, 2018), University of North Texas Libraries, Digital Library, digital.library.unt.edu; crediting UNT Libraries Government Documents Department.