Protein 4.1 Explained

Protein 4.1, (Erythrocyte membrane protein band 4.1), is a protein associated with the cytoskeleton that in humans is encoded by the EPB41 gene. Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in regulating membrane physical properties of mechanical stability and deformability by stabilizing spectrin-actin interaction. Protein 4.1 (80 kD) interacts with spectrin and short actin filaments to form the erythrocyte membrane skeleton. Mutations of spectrin and protein 4.1 are associated with elliptocytosis or spherocytosis and anemia of varying severity.

Clinical significance

Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Inherited as an autosomal dominant, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton. The form discussed here is the one found in the 1950s to be linked to Rh blood group and more recently shown to be caused by a defect in protein 4.1. 'Rh-unlinked' forms of elliptocytosis are caused by mutation in the alpha-spectrin gene (MIM 182860), the beta-spectrin gene (MIM 182870), or the band 3 gene (MIM 109270) [supplied by OMIM].^[1]

Interactions

Protein 4.1 has been shown to interact with:

• CENPJ,^[2]
• EIF3G^[3]
• NUMA1,^[4] and
• TJP2.^[5]

See also

• Elliptocytosis

Further reading

• Conboy JG . Structure, function, and molecular genetics of erythroid membrane skeletal protein 4.1 in normal and abnormal red blood cells. . Semin. Hematol. . 30 . 1 . 58–73 . 1993 . 8434260 .
• Calinisan V, Gravem D, Chen RP, Brittin S, Mohandas N, Lecomte MC, Gascard P . New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium. . Front. Biosci. . 11 . 1646–66 . 2006 . 16368544 . 10.2741/1911 . 26325962 . free .
• Dalla Venezia N, Gilsanz F, Alloisio N, Ducluzeau MT, Benz EJ, Delaunay J . Homozygous 4.1(-) hereditary elliptocytosis associated with a point mutation in the downstream initiation codon of protein 4.1 gene. . J. Clin. Invest. . 90 . 5 . 1713–7 . 1992 . 1430200 . 443228 . 10.1172/JCI116044 .
• Jöns T, Drenckhahn D . Identification of the binding interface involved in linkage of cytoskeletal protein 4.1 to the erythrocyte anion exchanger. . EMBO J. . 11 . 8 . 2863–7 . 1992 . 1639060 . 556766 . 10.1002/j.1460-2075.1992.tb05354.x.
• Subrahmanyam G, Bertics PJ, Anderson RA . Phosphorylation of protein 4.1 on tyrosine-418 modulates its function in vitro. . Proc. Natl. Acad. Sci. U.S.A. . 88 . 12 . 5222–6 . 1991 . 1647028 . 51844 . 10.1073/pnas.88.12.5222 . 1991PNAS...88.5222S . free .
• Conboy JG, Chan JY, Chasis JA, Kan YW, Mohandas N . Tissue- and development-specific alternative RNA splicing regulates expression of multiple isoforms of erythroid membrane protein 4.1. . J. Biol. Chem. . 266 . 13 . 8273–80 . 1991 . 10.1016/S0021-9258(18)92973-X . 2022644 . free .
• Horne WC, Prinz WC, Tang EK . Identification of two cAMP-dependent phosphorylation sites on erythrocyte protein 4.1. . Biochim. Biophys. Acta . 1055 . 1 . 87–92 . 1990 . 2171679 . 10.1016/0167-4889(90)90095-U .
• Conboy J, Marchesi S, Kim R, Agre P, Kan YW, Mohandas N . Molecular analysis of insertion/deletion mutations in protein 4.1 in elliptocytosis. II. Determination of molecular genetic origins of rearrangements. . J. Clin. Invest. . 86 . 2 . 524–30 . 1990 . 2384598 . 296755 . 10.1172/JCI114739 .
• Inaba M, Maede Y . O-N-acetyl-D-glucosamine moiety on discrete peptide of multiple protein 4.1 isoforms regulated by alternative pathways. . J. Biol. Chem. . 264 . 30 . 18149–55 . 1989 . 10.1016/S0021-9258(19)84689-6 . 2808371 . free .
• Korsgren C, Cohen CM . Associations of human erythrocyte band 4.2. Binding to ankyrin and to the cytoplasmic domain of band 3. . J. Biol. Chem. . 263 . 21 . 10212–8 . 1988 . 10.1016/S0021-9258(19)81500-4 . 2968981 . free .
• Conboy JG, Chan J, Mohandas N, Kan YW . Multiple protein 4.1 isoforms produced by alternative splicing in human erythroid cells. . Proc. Natl. Acad. Sci. U.S.A. . 85 . 23 . 9062–5 . 1988 . 3194408 . 282663 . 10.1073/pnas.85.23.9062 . 1988PNAS...85.9062C . free .
• Book: Tang TK, Leto TL, Marchesi VT, Benz EJ . Molecular Biology of Hemopoiesis . Expression of Specific Isoforms of Protein 4.1 in Erythroid and Non-Erythroid Tissues . 241 . 81–95 . 3223413 . 10.1007/978-1-4684-5571-7_12 . Advances in Experimental Medicine and Biology . 1988 . 978-1-4684-5573-1 .
• Tang TK, Leto TL, Correas I, Alonso MA, Marchesi VT, Benz EJ . Selective expression of an erythroid-specific isoform of protein 4.1. . Proc. Natl. Acad. Sci. U.S.A. . 85 . 11 . 3713–7 . 1988 . 3375238 . 280288 . 10.1073/pnas.85.11.3713 . 1988PNAS...85.3713T . free .
• Conboy J, Kan YW, Shohet SB, Mohandas N . Molecular cloning of protein 4.1, a major structural element of the human erythrocyte membrane skeleton. . Proc. Natl. Acad. Sci. U.S.A. . 83 . 24 . 9512–6 . 1987 . 3467321 . 387170 . 10.1073/pnas.83.24.9512 . free .
• Correas I, Speicher DW, Marchesi VT . Structure of the spectrin-actin binding site of erythrocyte protein 4.1. . J. Biol. Chem. . 261 . 28 . 13362–6 . 1986 . 10.1016/S0021-9258(18)69313-5 . 3531202 . free .
• Tchernia G, Mohandas N, Shohet SB . Deficiency of skeletal membrane protein band 4.1 in homozygous hereditary elliptocytosis. Implications for erythrocyte membrane stability. . J. Clin. Invest. . 68 . 2 . 454–60 . 1981 . 6894932 . 370818 . 10.1172/JCI110275 .
• Schischmanoff PO, Winardi R, Discher DE, Parra MK, Bicknese SE, Witkowska HE, Conboy JG, Mohandas N . Defining of the minimal domain of protein 4.1 involved in spectrin-actin binding. . J. Biol. Chem. . 270 . 36 . 21243–50 . 1995 . 7673158 . 10.1074/jbc.270.36.21243 . free .
• Lue RA, Marfatia SM, Branton D, Chishti AH . Cloning and characterization of hdlg: the human homologue of the Drosophila discs large tumor suppressor binds to protein 4.1. . Proc. Natl. Acad. Sci. U.S.A. . 91 . 21 . 9818–22 . 1994 . 7937897 . 44908 . 10.1073/pnas.91.21.9818 . 1994PNAS...91.9818L . free .
• Conboy JG, Chasis JA, Winardi R, Tchernia G, Kan YW, Mohandas N . An isoform-specific mutation in the protein 4.1 gene results in hereditary elliptocytosis and complete deficiency of protein 4.1 in erythrocytes but not in nonerythroid cells. . J. Clin. Invest. . 91 . 1 . 77–82 . 1993 . 8423235 . 329997 . 10.1172/JCI116203 .

Notes and References

1. Web site: Entrez Gene: EPB41 erythrocyte membrane protein band 4.1 (elliptocytosis 1, RH-linked).
2. Hung LY, Tang CJ, Tang TK . Protein 4.1 R-135 interacts with a novel centrosomal protein (CPAP) which is associated with the gamma-tubulin complex . Mol. Cell. Biol. . 20 . 20 . 7813–25 . October 2000 . 11003675 . 86375 . 10.1128/mcb.20.20.7813-7825.2000.
3. Hou CL . Tang Cj . Roffler SR . Tang TK . Protein 4.1R binding to eIF3-p44 suggests an interaction between the cytoskeletal network and the translation apparatus . Blood . 96 . 2 . 747–53 . July 2000 . 10.1182/blood.V96.2.747.014k19_747_753 . 2024-04-10 . 10887144 .
4. Mattagajasingh SN, Huang SC, Hartenstein JS, Snyder M, Marchesi VT, Benz EJ . A nonerythroid isoform of protein 4.1R interacts with the nuclear mitotic apparatus (NuMA) protein . J. Cell Biol. . 145 . 1 . 29–43 . April 1999 . 10189366 . 2148212 . 10.1083/jcb.145.1.29.
5. Mattagajasingh SN, Huang SC, Hartenstein JS, Benz EJ . Characterization of the interaction between protein 4.1R and ZO-2. A possible link between the tight junction and the actin cytoskeleton . J. Biol. Chem. . 275 . 39 . 30573–85 . September 2000 . 10874042 . 10.1074/jbc.M004578200 . free .