The complementary DNA (cDNA) of the RPSA gene is formed by the assembly of seven exons, six of which correspond to the coding sequence. 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. The structure of the N-domain of RPSA is similar to those of prokaryotic RPS2. 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.
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.
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. (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. (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.
RPSA was initially identified as a laminin binding protein. Both recombinant N-domain and C-domain of RPSA bind laminin in vitro, and they bind with similar dissociation constants (300 nM).
Both RPSA and laminin belong to the heparin/heparan sulfate interactome. 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.
RPSA is a potential cellular receptor for several pathogenic Flaviviruses, including the dengue virus (DENV), and Alphaviruses, including the Sindbis virus (SINV). The N-domain of RPSA includes a binding site for SINV in vitro. 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.
RPSA is also a receptor for small molecules. (i) RPSA binds aflatoxin B1 both in vivo and in vitro. (ii) RPSA is a receptor for epigallocatechin-gallate (EGCG), which is a major constituent of green tea and has many health related effects. EGCG binds only to the N-domain of RPSA in vitro, with a dissociation constant of 100 nM, but not to its C-domain.
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