Laminins, a family of extracellular matrixglycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Many of the effects of laminin are mediated through interactions with cell surface receptors. These receptors include members of the integrin family, as well as non-integrin laminin-binding proteins. The RPSA gene encodes a multifunctional protein, which is both a ribosomal protein and a high-affinity, non-integrin laminin receptor. This protein has been variously called Ribosomal protein SA; RPSA; LamR; LamR1; 37 kDa Laminin Receptor Precursor; 37LRP; 67 kDa Laminin Receptor; 67LR; 37/67 kDa Laminin Receptor; LRP/LR; LBP/p40; and p40 ribosome-associated protein. Ribosomal protein SA and RPSA are the approved name and symbol. The amino acidsequence of RPSA is highly conserved through evolution, suggesting a key biological function. It has been observed that the level of RPSA transcript is higher in coloncarcinomatissue and lung cancer cell lines than their normal counterparts. Also, there is a correlation between the upregulation of this polypeptide in cancer cells and their invasive and metastatic phenotype. Multiple copies of the RPSA gene exist; however, most of them are pseudogenes thought to have arisen from retropositional events. Two alternatively spliced transcript variants encoding the same protein have been found for this gene.[3]
Structure and stability
The complementary DNA (cDNA) of the RPSA gene is formed by the assembly of seven exons, six of which correspond to the coding sequence.[2] The amino acid sequence of RPSA, deduced from the sequence of its cDNA, includes 295 residues. RPSA can be sub-divided in two main domains: an N-domain (residues 1-209), which corresponds to exons 2-5 of the gene, and a C-domain (residues 210-295), which corresponds to exons 6-7. The N-domain of RPSA is homologous to the ribosomal protein S2 (RPS2) of prokaryotes. It contains a palindromic sequence 173LMWWML178 which is conserved in all metazoans. Its C-domain is highly conserved in vertebrates. The amino acid sequence of RPSA is 98% identical in all mammals. RPSA is a ribosomal protein which has acquired the function of laminin receptor during evolution.[4][5] The structure of the N-domain of RPSA is similar to those of prokaryotic RPS2.[6] The C-domain is intrinsically disordered in solution. The N-domain is monomeric in solution and unfolds according to a three state equilibrium. The folding intermediate is predominant at 37 °C.[7]
Interactions
Several interactions of RPSA that had originally been discovered by methods of cellular biology, have subsequently been confirmed by using recombinant derivatives and in vitro experiments. The latter have shown that the folded N-domain and disordered C-domain of RPSA have both common and specific functions.[8]
RPSA binds to proteins that are involved in the translation of the genetic code. (i) Yeast two-hybrid screens have shown that RPSA binds to Ribosomal protein S21 of the 40S small ribosomal subunit.[9][10] (ii) Serial deletions of RPSA have shown that the segment of residues 236-262, included in the C-domain, is involved in the interaction between RPSA and the 40S subunit of ribosome.[11] (iii) Studies that were based on nuclear magnetic resonance spectroscopy (NMR), have shown that the anticodon binding domain of Lysyl-tRNA synthetase binds directly to the C-domain of RPSA.[12]
RPSA was initially identified as a laminin binding protein.[13][14] Both recombinant N-domain and C-domain of RPSA bind laminin in vitro, and they bind with similar dissociation constants (300 nM).[6][8]
Both RPSA and laminin belong to the heparin/heparan sulfate interactome.[15] Heparin binds in vitro to the N-domain of RPSA but not to its C-domain. Moreover, the C-domain of RPSA and heparin compete for binding to laminin, which shows that the highly acidic C-domain of RPSA mimicks heparin (and potentially heparan sulfates) for the binding to laminin.[8]
RPSA is a potential cellular receptor for several pathogenic Flaviviruses, including the dengue virus (DENV),[16][17] and Alphaviruses, including the Sindbis virus (SINV).[18] The N-domain of RPSA includes a binding site for SINV in vitro.[6] The N-domain also includes weak binding sites for recombinant domain 3 (ED3, residues 296-400) from the envelope proteins of two Flaviviruses, West-Nile virus and serotype 2 of DENV. The C-domain includes weak binding sites for domain 3 of the yellow fever virus (YFV) and of serotypes 1 and 2 of DENV. In contrast, domain 3 from the Japanese encephalitis virus does not appear to bind RPSA in vitro.[8]
RPSA is also a receptor for small molecules. (i) RPSA binds aflatoxin B1 both in vivo and in vitro.[19] (ii) RPSA is a receptor for epigallocatechin-gallate (EGCG), which is a major constituent of green tea and has many health related effects.[20][21] EGCG binds only to the N-domain of RPSA in vitro, with a dissociation constant of 100 nM, but not to its C-domain.[8]
References
↑Satoh K, Narumi K, Sakai T, Abe T, Kikuchi T, Matsushima K, Sindoh S, Motomiya M (Jul 1992). "Cloning of 67-kDa laminin receptor cDNA and gene expression in normal and malignant cell lines of the human lung". Cancer Lett. 62 (3): 199–203. doi:10.1016/0304-3835(92)90096-E. PMID1534510.
↑ 2.02.1Jackers P, Minoletti F, Belotti D, Clausse N, Sozzi G, Sobel ME, Castronovo V (Sep 1996). "Isolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21.3". Oncogene. 13 (3): 495–503. PMID8760291.
↑DiGiacomo, Vincent; Meruelo, Daniel (May 2016). "Looking into laminin receptor: critical discussion regarding the non-integrin 37/67-kDa laminin receptor/RPSA protein". Biological Reviews. 91 (2): 288–310. doi:10.1111/brv.12170.
↑Ardini E, Pesole G, Tagliabue E, Magnifico A, Castronovo V, Sobel ME, Colnaghi MI, Ménard S (August 1998). "The 67-kDa laminin receptor originated from a ribosomal protein that acquired a dual function during evolution". Molecular Biology and Evolution. 15 (8): 1017–25. doi:10.1093/oxfordjournals.molbev.a026000. PMID9718729.
↑Nelson J, McFerran NV, Pivato G, Chambers E, Doherty C, Steele D, Timson DJ (February 2008). "The 67 kDa laminin receptor: structure, function and role in disease". Bioscience Reports. 28 (1): 33–48. doi:10.1042/BSR20070004. PMID18269348.
↑ 6.06.16.2Jamieson KV, Wu J, Hubbard SR, Meruelo D (February 2008). "Crystal structure of the human laminin receptor precursor". The Journal of Biological Chemistry. 283 (6): 3002–5. doi:10.1074/jbc.C700206200. PMID18063583.
↑Ould-Abeih, MB; Petit-Topin, I; Zidane, N; Baron, B; Bedouelle, Hugues (Jun 2012). "Multiple folding states and disorder of ribosomal protein SA, a membrane receptor for laminin, anticarcinogens, and pathogens". Biochemistry. 51 (24): 4807–4821. doi:10.1021/bi300335r. PMID22640394.
↑Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (Sep 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–968. doi:10.1016/j.cell.2005.08.029. PMID16169070.
↑Sato M, Saeki Y, Tanaka K, Kaneda Y (Mar 1999). "Ribosome-associated protein LBP/p40 binds to S21 protein of 40S ribosome: analysis using a yeast two-hybrid system". Biochem. Biophys. Res. Commun. 256 (2): 385–390. doi:10.1006/bbrc.1999.0343. PMID10079194.
↑Malygin, AA; Babaylova, ES; Loktev, VB; Karpova, GG (2011). "A region in the C-terminal domain of ribosomal protein SA required for binding of SA to the human 40S ribosomal subunit". Biochimie. 93 (3): 612–617. doi:10.1016/j.biochi.2010.12.005. PMID21167900.
↑Cho, HY; Ul Mushtaq, A; Lee, JY; Kim, DG; Seok, MS; Jang, M; Han, BW; Kim, S; Jeon, YH (2014). "Characterization of the interaction between lysyl-tRNA synthetase and laminin receptor by NMR". FEBS Lett. 588 (17): 2851–2858. doi:10.1016/j.febslet.2014.06.048. PMID24983501.
↑Rao, NC; Barsky, SH; Terranova, VP; Liotta, LA (1983). "Isolation of a tumor cell laminin receptor". Biochem. Biophys. Res. Commun. 111 (3): 804–808. doi:10.1016/0006-291X(83)91370-0. PMID6301485.
↑Zhuang, Z; Huang, Y; Yang, Y; Wang, S (2016). "Identification of AFB1-interacting proteins and interactions between RPSA and AFB1". J. Hazard. Mater. 301: 297–303. doi:10.1016/j.jhazmat.2015.08.053. PMID26372695.
↑Tachibana, H; Koga, K; Fujimura, Y; Yamada, K (2004). "A receptor for green tea polyphenol EGCG". Nat. Struct. Mol. Biol. 11 (4): 380–381. doi:10.1038/nsmb743. PMID15024383.
Selvamurugan N, Eliceiri GL (1996). "The gene for human E2 small nucleolar RNA resides in an intron of a laminin-binding protein gene". Genomics. 30 (2): 400–1. PMID8586453.
Vladimirov SN, Ivanov AV, Karpova GG, Musolyamov AK, Egorov TA, Thiede B, Wittmann-Liebold B, Otto A (1996). "Characterization of the human small-ribosomal-subunit proteins by N-terminal and internal sequencing, and mass spectrometry". Eur. J. Biochem. 239 (1): 144–149. doi:10.1111/j.1432-1033.1996.0144u.x. PMID8706699.
Clausse N, Jackers P, Jarès P, Joris B, Sobel ME, Castronovo V (1997). "Identification of the active gene coding for the metastasis-associated 37LRP/p40 multifunctional protein". DNA Cell Biol. 15 (12): 1009–1023. doi:10.1089/dna.1996.15.1009. PMID8985115.
Kenmochi N, Kawaguchi T, Rozen S, Davis E, Goodman N, Hudson TJ, Tanaka T, Page DC (1998). "A map of 75 human ribosomal protein genes". Genome Res. 8 (5): 509–23. doi:10.1101/gr.8.5.509. PMID9582194.
de Manzoni G, Guglielmi A, Verlato G, Tomezzoli A, Pelosi G, Schiavon I, Cordiano C (1998). "Prognostic significance of 67-kDa laminin receptor expression in advanced gastric cancer". Oncology. 55 (5): 456–460. doi:10.1159/000011895. PMID9732225.
Sato M, Saeki Y, Tanaka K, Kaneda Y (1999). "Ribosome-associated protein LBP/p40 binds to S21 protein of 40S ribosome: analysis using a yeast two-hybrid system". Biochem. Biophys. Res. Commun. 256 (2): 385–390. doi:10.1006/bbrc.1999.0343. PMID10079194.
Canfield SM, Khakoo AY (1999). "The nonintegrin laminin binding protein (p67 LBP) is expressed on a subset of activated human T lymphocytes and, together with the integrin very late activation antigen-6, mediates avid cellular adherence to laminin". J. Immunol. 163 (6): 3430–40. PMID10477615.
Donaldson EA, McKenna DJ, McMullen CB, Scott WN, Stitt AW, Nelson J (2000). "The expression of membrane-associated 67-kDa laminin receptor (67LR) is modulated in vitro by cell-contact inhibition". Mol. Cell Biol. Res. Commun. 3 (1): 53–59. doi:10.1006/mcbr.2000.0191. PMID10683318.
Pedraza C, Geberhiwot T, Ingerpuu S, Assefa D, Wondimu Z, Kortesmaa J, Tryggvason K, Virtanen I, Patarroyo M (2000). "Monocytic cells synthesize, adhere to, and migrate on laminin-8 (alpha 4 beta 1 gamma 1)". J. Immunol. 165 (10): 5831–8. doi:10.4049/jimmunol.165.10.5831. PMID11067943.
Waltregny D, de Leval L, Coppens L, Youssef E, de Leval J, Castronovo V (2002). "Detection of the 67-kD laminin receptor in prostate cancer biopsies as a predictor of recurrence after radical prostatectomy". Eur. Urol. 40 (5): 495–503. doi:10.1159/000049825. PMID11752855.