Long interspersed nuclear elements-1 (L1) is an active autonomous retrotransposon. L1 encodes two proteins in different open reading frames. The protein expressed by the first open reading frame (ORF1p) may be an RNA binding and chaperone protein. It contains a three-stranded coiled coil (3SCC) domain near the N-terminus that facilitates formation of the biologically active homotrimer. This 3SCC domain is composed of seven amino acid (labelled a,b,c,d,e,f,and g within the heptad) repeats and a stammer insertion of three extra residues that modifies the helical structure. Cysteine residues are located within the 3SCC at three hydrophobic positions (2 a- and 1 d-layer sites) within this domain. Based on sequence and crystallographic comparison to our de novo designed peptides that contain cysteine layers in the hydrophobic core of 3SCCs, we propose that ORF1p binds transition or heavy metals with relatively high affinities, a feature that has not been previously recognized. We first demonstrate the geometric similarities between the ORF1p and our de novo designed construct tris(cysteine) layers. We propose that due to the high degree of similarity, that the ORF1p binds metal ions in a similar fashion as TRI and Grand constructs. Thus, the metal binding properties of these tris(cysteine) environments will be reviewed and their potential application to ORF1p metal binding will be discussed. This has major implications for ORF1p coiled coil domain stability and dynamics, ultimately significantly impacting the resulting biological activity, and a largely unexplored avenue of the chemical biology of DNA mobile elements.

Control of metal geometries within de novo designed three-stranded coiled coils

256th National Meeting (2018)

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