The `Spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families

Abstract

IntroductionA recently discovered family of cytoskeletal proteins belongs within both the spectrin and plakin superfamilies. These superfamilies consist of proteins that contribute to the linkage between the plasma membrane and the cytoskeleton. Spectrin superfamily members bind and crosslink actin filaments and attach these to membrane receptors. Members of the plakin superfamily were first identified as components of desmosomes and hemidesmosomes, connecting the adhesion receptors to intermediate filaments, but they also can crosslink different cytoskeletal elements. At present we know of two mammalian genes that encode related members of the new family, BPAG1 and MACF1, and a single Drosophila gene, short stop (shot) (Figs 1 and 2). Each of these is also known by other names, which reflects their independent discovery by different groups: MACF1 is known as ACF7, MACF, MACF7, macrophin, trabeculin α and ABP620; BPAG1 is known as dystonin and MACF2; shot is known as kakapo, kopupu and groovin (Brown et al., 1995a;Bernier et al., 1996;Becker et al., 1997;Prout et al., 1997;Gregory and Brown, 1998;Strumpf and Volk, 1998;Walsh and Brown, 1998;Leung et al., 1999b; Okuda et al., 1999;Sun et al., 1999;Yang et al., 1999;Lee et al., 2000;Leung et al., 2001b;Sun et al., 2001). A single Caenorhabditis elegans gene can also be identified in the genomic sequence; this is currently annotated as three genes: ZK1151.1, ZK1151.2 and ZK1151.3 (C. elegans Sequencing Consortium, 1998). Because the proteins encoded by these genes share features with both spectrin and plakin superfamily members and may represent the evolutionary precursor of the plakins (see below), we refer to them as spectraplakins to highlight their dual nature. Here we discuss the possible functions of spectraplakins indicated by their sequences and by biochemical and genetic studies, extrapolating from the functions of homologous cytoskeletal proteins.Spectraplakins in various species were identified independently in quite different contexts. In the fly, the spectraplakin shot emerged from genetic screens aimed at identifying genes required for integrin-mediated adhesion (Prout et al., 1997;Gregory and Brown, 1998;Strumpf and Volk, 1998) or axon extension (Van Vactor et al., 1993;Lee et al., 2000). The vertebrate spectraplakin BPAG1/dystonin was identified as a protein targeted by the autoimmune disease bullous pemphigoid in humans (Minoshima et al., 1991) and as the gene affected in the disease dystonia musculorum in mice (Brown et al., 1995a;Guo et al., 1995). Diverse motifs within spectraplakin isoformsThe full complexity of the genes producing spectraplakins has gradually emerged. The first spectraplakin product characterised, BPAG1e, is a substantial protein of 2649 residues encoded by an 8.7 kb mRNA; yet this appears to be the smallest and simplest of the spectraplakin products (Fig. 3). The previous lack of awareness of the larger spectraplakins is likely to have led to erroneous conclusions being drawn in the older literature about the functions of th...

The flare Gene, Which Encodes the AIP1 Protein of Drosophila, Functions to Regulate F-Actin Disassembly in Pupal Epidermal Cells

“…An alternative hypothesis is that flr and tsr mutations result in an increased concentration of F-actin and this in turn results in increased tubulin staining. There is a substantial literature on proteins that mediate connections between the actin and microtubule cytoskeletons (e.g., Roper et al 2002;Miller et al 2004) although none of the interactions are as dramatic as the one we found. One example of a gene that encodes a protein that links the actin and microtubule cytoskeletons and that function in the morphogenesis of the fly wing is short stop (shot), which encodes a spectraplakin family member.…”

“…One example of a gene that encodes a protein that links the actin and microtubule cytoskeletons and that function in the morphogenesis of the fly wing is short stop (shot), which encodes a spectraplakin family member. However, it is unlikely that this protein plays an important role in linking the actin and microtubule cytoskeletons during hair morphogenesis as shot mutant wing cells produce normal-looking hairs (Roper et al 2002).…”

The making of hemidesmosome structures in vivo

“…Vertebrates contain plectin and two giant spectraplakins (Macf1 and Dst); cephalochordates, urochordates, nematodes, and insects contain a single predicted spectraplakin locus (C. elegans vab-10 and D. melanogaster shot) (Roper et al, 2002). Alternative splicing of the spectraplakin locus generates an isoform with the structure of vertebrate Plectin and BPAG1e in C. elegans, but not in D. melanogaster (no information currently available for C. intestinalis, B. floridae, or S. mansoni) (Roper et al, 2002;Bosher et al, 2003). The zebrafish genome encodes homologues of all mammalian hemidesmosome components, suggesting that it can form type I hemidesmosomes.…”

Functional and Genetic Analysis of Spectraplakins in Drosophila

“…The plakinhomology domain (six to nine spectrin-like repeats and an SH3 domain embedded in the 5th repeat) links to transmembrane collagens and β4 integrin in BPAG1e (Aumailley, Has, Tunggal, & Bruckner-Tuderman, 2006;Koster, Geerts, Favre, Borradori, & Sonnenberg, 2003) and mediates compartmentalization of transmembrane proteins in fly neurons (Bottenberg et al, 2009). The spectrin/dystrophin repeat rod domain likely acts as spacer or in dimerization (Bottenberg et al, 2009;Leung et al, 1999;Machnicka et al, 2014;R€ oper, Gregory, & Brown, 2002). Plectin-repeat domains (PRD) typically bind intermediate filaments (Aumailley et al, 2006;Jefferson et al, 2004).…”

“…As illustrated for Shot in Fig. 1A, the genomic loci encoding spectraplakins generate numerous isoforms with up to seven recognized functional domains that establish them as true members of three protein families, the plakins, spectrins, and Gas2-like proteins (Brown, 2008;R€ oper et al, 2002;Suozzi, Wu, & Fuchs, 2012):…”