3 | Microprotein Structure and Function
Dozens of human microproteins, and many more in model organisms, have
now been assigned function at the molecular, cellular, and/or organismal
level. CRISPR screens have implicated hundreds of sORFs in cell survival
and proliferation. Experimental approaches are yielding insights into
the roles of microproteins in biological processes and disease, which
have been extensively reviewed. Recently emerging trends in microprotein
function include roles in immunity and inflammation, mitochondrial
functions and energetics, adiposity, microbial carbon metabolism, and
cancer initiation and progression, among others. Nonetheless, the vast
majority of recently discovered microproteins remain entirely
uncharacterized in mechanistic detail. This is in large part because
bioinformatic predictions of sORF function are challenging—even when
they exhibit signatures of conservation in multiple species,
microproteins tend to lack primary sequence homology to proteins of
known function. While three-dimensional structure prediction and
elucidation are likely to provide important insights into microprotein
functions, structures of microproteins have not yet been examined on
scale. However, the number of experimentally determined structures of
microproteins, in isolation or in complex with their effectors, is
growing, and general trends have begun to emerge, which we will describe
in this section. First, we discuss a subclass of single-pass
alpha-helical transmembrane microproteins, many of which are
evolutionarily novel, and some of which bind to and regulate important
transporters. Next, we consider examples of microproteins with solved or
predicted structures and the potential relevance to their functions.
Last, we will examine several intrinsically disordered microproteins
that undergo regulatory protein-protein interactions.