title: Nanoparticle as signaling protein mimic: robust structural and functional modulation of CaMKII upon specific binding to fullerene C60 nanocrystals.
abstract: In a biological environment, nanoparticles encounter and interact with thousands of proteins, forming a protein corona on the surface of the nanoparticles, but these interactions are oftentimes perceived as nonspecific protein adsorption, with protein unfolding and deactivation as the most likely consequences. The potential of a nanoparticle-protein interaction to mimic a protein-protein interaction in a cellular signaling process, characterized by stringent binding specificity and robust functional modulation for the interacting protein, has not been adequately demonstrated. Here, we show that water-suspended fullerene C60 nanocrystals (nano-C60) interact with and modulate the function of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), a multimeric intracellular serine/threonine kinase central to Ca(2+) signal transduction, in a fashion that rivals the well-documented interaction between the NMDA (N-methyl-d-aspartate) receptor subunit NR2B protein and CaMKII. The stable high-affinity binding of CaMKII to distinct sites on nano-C60, mediated by amino acid residues D246 and K250 within the catalytic domain of CaMKIIα, but not the nonspecific adsorption of CaMKII to diamond nanoparticles, leads to functional consequences reminiscent of the NR2B-CaMKII interaction, including generation of autonomous CaMKII activity after Ca(2+) withdrawal, calmodulin trapping and CaMKII translocation to postsynaptic sites. Our results underscore the critical importance of specific interactions between nanoparticles and cellular signaling proteins, and the ability of nano-C60 to sustain the autonomous kinase activity of CaMKII may have significant implications for both the biosafety and the potential therapeutic applications of fullerene C60.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science & Technology of China , Hefei, Anhui 230027, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Miao
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Bian
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Fang
authors.initials: F
authors.lastname: Zheng
authors.forename: Na
authors.initials: N
authors.lastname: Man
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Yunjiao
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Longping
authors.initials: L
authors.lastname: Wen
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D032701:Biomimetics; D019556:COS Cells; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000737:chemistry*; D004705:Endocytosis; D000939:Epitopes / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism; D037741:Fullerenes / Q000737:chemistry*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D000596:Amino Acids; D000939:Epitopes; D037741:Fullerenes; C121001:NR2B NMDA receptor; D011506:Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C069837:fullerene C60