Selenium-Encoded Isotopic Signature Targeted Profiling

Selenium
(Se), as an essential trace element, plays crucial roles
in many organisms including humans. The biological functions of selenium
are mainly mediated by selenoproteins, a unique class of selenium-containing
proteins in which selenium is inserted in the form of selenocysteine.
Due to their low abundance and uneven tissue distribution, detection
of selenoproteins within proteomes is very challenging, and therefore
functional studies of these proteins are limited. In this study, we
developed a computational method, named as selenium-encoded isotopic
signature targeted profiling (SESTAR), which utilizes the distinct
natural isotopic distribution of selenium to assist detection of trace
selenium-containing signals from shotgun-proteomic data. SESTAR can
detect femtomole quantities of synthetic selenopeptides in a benchmark
test and dramatically improved detection of native selenoproteins
from tissue proteomes in a targeted profiling mode. By applying SESTAR
to screen publicly available datasets from Human Proteome Map, we
provide a comprehensive picture of selenoprotein distributions in
human primary hematopoietic cells and tissues. We further demonstrated
that SESTAR can aid chemical-proteomic strategies to identify additional
selenoprotein targets of RSL3, a canonical inducer of cell ferroptosis.
We believe SESTAR not only serves as a powerful tool for global profiling
of native selenoproteomes, but can also work seamlessly with chemical-proteomic
profiling strategies to enhance identification of target proteins,
post-translational modifications, or protein–protein interactions.