%0 Journal Article
%T Insights into the Function of the Unstructured N-Terminal Domain of Proteins 4.1R and 4.1G in Erythropoiesis
%A Wataru Nunomura
%A Philippe Gascard
%A Yuichi Takakuwa
%J International Journal of Cell Biology
%D 2011
%I Hindawi Publishing Corporation
%R 10.1155/2011/943272
%X Membrane skeletal protein 4.1R is the prototypical member of a family of four highly paralogous proteins that include 4.1G, 4.1N, and 4.1B. Two isoforms of 4.1R (4.1R135 and 4.1R80), as well as 4.1G, are expressed in erythroblasts during terminal differentiation, but only 4.1R80 is present in mature erythrocytes. One goal in the field is to better understand the complex regulation of cell type and isoform-specific expression of 4.1 proteins. To start answering these questions, we are studying in depth the important functions of 4.1 proteins in the organization and function of the membrane skeleton in erythrocytes. We have previously reported that the binding profiles of 4.1R80 and 4.1R135 to membrane proteins and calmodulin are very different despite the similar structure of the membrane-binding domain of 4.1G and 4.1R135. We have accumulated evidence for those differences being caused by the N-terminal 209 amino acids headpiece region (HP). Interestingly, the HP region is an unstructured domain. Here we present an overview of the differences and similarities between 4.1 isoforms and paralogs. We also discuss the biological significance of unstructured domains. 1. 4.1R in the Erythrocyte Membrane Skeleton The membrane skeleton, which underlies the erythrocyte plasma membrane, is made of a spectrin/actin lattice anchored to various transmembrane proteins via two specialized cytoskeletal proteins, 4.1R and red blood cell ankyrin, ankyrin-R [1]. 4.1R80 stabilizes horizontal interactions between spectrin heterodimers (¦Á2-¦Â2) and short actin (~14 molecules) filaments. Actin filaments interact with numerous accessory proteins, such as tropomyosin, myosin, tropomodulin, and adducin [1], which ensure reorganization of actin filaments. 4.1R80 interacts also with the transmembrane protein, glycophorin C (GPC) and with the membrane-associated guanylate kinase (MAGUK) protein p55, which also acts as an erythrocyte scaffolding protein (Figure 1). Figure 1: Structure of human erythrocyte membrane. Spectrin dimers underlying the membrane interact with transmembrane proteins band 3 through ankyrin and glycophorin C (GPC) through an actin complex and protein 4.1R 80 (4.1R 80). 4.1R 80 also forms a ternary complex with p55 and GPC. CaM binds to 4.1R 80 in a Ca 2+-independent manner. 1.1. GPC GPC is 32£¿kDa single transmembrane protein expressed at ~50,000£¿100,000 molecules/erythrocyte. The cytoplasmic domain consists of 47 amino acids residues (ID: P04921). The R82HK sequence has been identified as the 4.1R binding sequence [2¨C4]. This RHK motif is highly conserved in the
%U http://www.hindawi.com/journals/ijcb/2011/943272/