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.