Molecules in focus
RAP55: Insights into an evolutionarily conserved protein family

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Abstract

The RAP55 protein family is evolutionarily conserved in eukaryotes. Two highly conserved paralogues, RAP55A and RAP55B, exist in vertebrates; their functional properties and expression patterns remain to be compared. RAP55 proteins share multiple domains: the LSm14 domain, a serine/threonine rich region, an FDF (phenylalanine–aspartate–phenylalanine) motif, an FFD-TFG box and RGG (arginine–glycine–glycine) repeats. Together these domains are responsible for RAP55 proteins participating in translational repression, incorporation into mRNP particles, protein–protein interactions, P-body formation and stress granule localisation. All RAP55A proteins localise to P-body-like complexes either in the germline or in somatic cells. Xenopus laevis RAP55B has been shown to be part of translationally repressed mRNP complexes in early oocytes. Together these findings suggest that this protein family has evolved a common and fundamental role in the control of mRNA translation. Furthermore human RAP55A is an autoantigen detected in the serum of patients with primary biliary cirrhosis (PBC). The link between RAP55A, P-bodies and PBC remains to be elucidated.

Introduction

RAP55 was first discovered in the newt Pleurodeles waltl and in Xenopus laevis as an RNA-associated protein of 55 kDa and initially thought to be oocyte-specific in its expression (Lieb et al., 1998). A defining feature of RAP55 is a highly conserved ‘LSm14 domain’ present in a range of proteins called the LSm14 or Scd6 family (Albrecht and Lengauer, 2004). Eukaryotic RAP55 proteins include Sum2p in Schizosaccharomyces pombe; Scd6 in Saccharomyces cerevisiae; CAR-1 in Caenorhabditis elegans; Trailer Hitch (Tral) in Drosophila melanogaster; xRAP55 in X. laevis; mTral in mouse and hRAP55 in humans (Boag et al., 2005). In vertebrates, the family has further evolved into two RAP55 proteins paralogues, named RAP55A and RAP55B. To date most studies have focused on RAP55A; however the functional properties and expression of RAP55A and RAP55B remain to be compared.

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Structure

All RAP55 proteins are characterised by a multidomain organisation composed of the LSm14 domain; a serine/threonine (Ser/Thr)-rich region; an FDF (phenylalanine-aspartate-phenylalanine) motif; an FFD-TFG box and arginine-glycine-glycine (RGG) repeats (Fig. 1A). RAP55 proteins share a well-conserved N-terminus, whose defining feature is the LSm14 domain (Albrecht and Lengauer, 2004); whereas the C-terminus and the central region are less well conserved. In general, Sm and Sm-like (LSm) proteins

Expression and regulation

Human RAP55A was first detected in the serum of patients with the autoimmune disease primary biliary cirrhosis (PBC) in which the autoimmune serum detected P-bodies (Table 1) (Yang et al., 2006). P-bodies are cytoplasmic foci conserved across eukaryotes that contain translationally repressed mRNAs and enzymes that are part of the 5′–3′ mRNA decay machinery; including the decapping enzymes Dcp1 and Dcp2, decapping activators Edc3, LSm1–7, the RNA helicase rck/p54, the deadenylase CCR4 and the

Biological function

Human and Xenopus RAP55A are essential for P-body assembly. In cells depleted of RAP55A P-bodies can no longer be detected (Tanaka et al., 2006, Yang et al., 2006). In contrast, depletion of Tral in Drosophila S2 cells does not affect P-body integrity, suggesting that RAP55A and Tral are not absolute functional equivalents. The domains responsible for the accumulation of the human RAP55A in P-bodies are the RGG repeats, the FDF domain and the FFD-TFG box (Yang et al., 2006). However, the

Possible relevance to disease

Primary biliary cirrhosis is a progressive autoimmune disease that predominantly affects middle-aged women. This disease is characterized by an inflammation and immune-mediated destruction of intrahepatic biliary ductules followed by hepatic fibrosis and liver failure (Kaplan and Gershwin, 2005). The causative agents are thought to include bacteria, viruses and chemicals. However, it is not clear how these could bring about PBC. The symptoms are general fatigue and pruritus (skin itching), but

Acknowledgments

Aline Marnef is supported by PhD studentship from the BBSRC, UK. We would also like to thank Nancy Standart for her helpful comments.

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