Site-selective photo crosslink to methyllysine readers via single electron transfer between sulfonium and tryptophan

ABSTRACT: Reader proteins play significant roles in cell signaling from site-specific lysine methylation, but the progress of new reader investigations is rather slow. Photoreactive crosslinkers enable reader identifications, but it requires laborious chemical synthesis for optimization of the photoreactive group placement. In addition, active intermediate such as nitrene and carbene may cause significant non-specific crosslinking. Here we report dimethylsulfonium as methyllysine mimic binds to specific readers and subsequently crosslinks to conserved tryptophan inside binding pocket via single electron transfer under UV irradiation. Because the σ-π electron-donor-acceptor interaction between sulfonium and indole is a key step, the crosslinking exhibits excellent tryptophan site-selectivity and orthogonality to distinct methyllysine readers. Moreover, excited tryptophan without proximate sulfonium leads to minimal non-specific crosslinking from relaxation. Consequently, this method could escalate discovery of methyllysine readers from complicated cell samples. Furthermore, this photo crosslinking concept could be expanded to develop more types of microenvironment-dependent conjugations to site-specific tryptophan.

ORGANISM(S): Homo Sapiens

SUBMITTER: Lihua Zhang  

PROVIDER: PXD049149 | iProX | Sun Feb 04 00:00:00 GMT 2024

REPOSITORIES: iProX