Crystal structure of a dimerization domain of human Caprin-1: insights into the assembly of an evolutionarily conserved ribonucleoprotein complex consisting of Caprin-1, FMRP and G3BP1.
Caprin-1 plays roles in many important biological processes, including cellular proliferation, innate immune response, stress response and synaptic plasticity. Caprin-1 has been implicated in several human diseases, including osteosarcoma, breast cancer, viral infection, hearing loss and neurodegenerative disorders. The functions of Caprin-1 depend on its molecular-interaction network. Direct interactions have been established between Caprin-1 and the fragile X mental retardation protein (FMRP), Ras GAP-activating protein-binding protein 1 (G3BP1) and the Japanese encephalitis virus (JEV) core protein. Here, crystal structures of a fragment (residues 132-251) of Caprin-1, which adopts a novel all-α-helical fold and mediates homodimerization through a substantial interface, are reported. Homodimerization creates a large and highly negatively charged concave surface suggestive of a protein-binding groove. The FMRP-interacting sequence motif forms an integral α-helix in the dimeric Caprin-1 structure in such a way that the binding of FMRP would not disrupt the homodimerization of Caprin-1. Based on insights from the structures and existing biochemical data, the existence of an evolutionarily conserved ribonucleoprotein (RNP) complex consisting of Caprin-1, FMRP and G3BP1 is proposed. The JEV core protein may bind Caprin-1 at the negatively charged putative protein-binding groove and an adjacent E-rich sequence to hijack the RNP complex.
Department of Chemistry and Biochemistry, Southern Illinois University, 1245 Lincoln Drive, Carbondale, IL 62901, USA.
Yuhong
Y
Wu
Department of Chemistry and Biochemistry, Southern Illinois University, 1245 Lincoln Drive, Carbondale, IL 62901, USA.
Jiang
J
Zhu
Department of Computer Science, Southern Illinois University, 1000 Faner Drive, Carbondale, IL 62901, USA.
Xiaolan
X
Huang
Department of Chemistry and Biochemistry, Southern Illinois University, 1245 Lincoln Drive, Carbondale, IL 62901, USA.
Zhihua
Z
Du
D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D004265:DNA Helicases; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D000072417:Protein Domains; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D016415:Sequence Alignment
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004265:DNA Helicases; D051860:Fragile X Messenger Ribonucleoprotein 1; D000075223:Poly-ADP-Ribose Binding Proteins; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; C486562:CAPRIN1 protein, human; C497683:FMR1 protein, human; C116070:G3BP1 protein, human
Caprin-1; Caprin-2; FMRP; G3BP1; JEV core protein; RNA stress granule