Regulation of protein function by interfering protein species

Most proteins do not function alone but act in protein complexes. For several transcriptional regulators, it is known that they have to homo- or heterodimerize prior to DNA binding. These protein interactions occur through defined protein-protein-interaction (PPI) domains. More than two decades ago, inhibitor of DNA binding (ID), a small protein containing a single helix-loop-helix (HLH) motif was identified. ID is able to interact with the larger DNA-binding basic helix-loop-helix (bHLH) transcription factors, but due to the lack of the basic domain required for DNA binding, ID traps bHLH proteins in non-functional complexes. Work in plants has, in the recent years, identified more small proteins acting in analogy to ID. A hallmark of these small negative acting proteins is the presence of a protein-interaction domain and the absence of other functional domains required for transcriptional activation or DNA binding. Because these proteins are often very small and function in analogy to microRNAs (meaning in a dominant-negative manner), we propose to refer to these protein species as ‘microProteins’ (miPs). miPs can be encoded in the genome as individual transcription units but can also be produced by alternative splicing. Other negatively acting proteins, consisting of more than one domain, have also been identified, and we propose to call these proteins ‘interfering proteins’ (iPs). The aim of this review is to state more precisely how to discriminate miPs from iPs. Therefore, we will highlight recent findings on both protein species and describe their mode of action. Furthermore, miPs have the ability to regulate proteins of diverse functions, emphasizing their value as biotechnological tools.