Microprotein

For a similar (if not identical) concept, see Micropeptide.

A microprotein (miP) is a small protein encoded from a small open reading frame (sORF),^[1] also known as sORF-encoded protein (SEP). They are a class of protein with a single protein domain. They are related to multidomain proteins.^[2] Microproteins regulate larger multidomain proteins at the post-translational level.^[3] Microproteins are analogous to microRNAs (miRNAs) and heterodimerize with their targets causing dominant and negative effects.^[4] In animals and plants, microproteins influence many biological processes.^[2] Because of their dominant effects on their targets, microproteins are currently under study for use in biotechnology.^[2]

History

The first miP was discovered during a research in the early 1990s on genes for basic helix–loop–helix (bHLH) transcription factors from a murine erythroleukaemia cell cDNA library.^[3] The protein was an inhibitor of DNA binding (ID protein), and negatively regulated the transcription factor complex.^[3] The protein was 16 kDa and consisted of a helix-loop-helix (HLH) domain.^[2] The microprotein formed bHLH/HLH heterodimers that disrupted the functional basic helix–loop–helix (bHLH) homodimers.^[2]

The first plant microprotein discovered was the LITTLE ZIPPER (ZPR) protein.^[2] The LITTLE ZIPPER protein contains a leucine zipper domain, but lacks the domains required for DNA binding and transcription activation.^[2] Thus, LITTLE ZIPPER protein is analogous to the ID protein.^[2] Although not all proteins are small, in 2011, this class of protein was given the name microproteins because their negative regulatory actions are similar to those of miRNAs.^[3]

The ID protein or proteins similar to ID are found in all animals.^[3] Plant microproteins are only found in higher orders.^[3] However, the homeodomain transcription factors that belong to the three-amino-acid loop-extension (TALE) family are targets of microproteins, and these homeodomain proteins are conserved in animals, plants, and fungi.^[3]

Structure

Microproteins generally feature a single protein domain.^[2][4] The active form is translated from smORF.^[1] smORF codons can be less than 100 codons.^[1] However, not all microproteins are small, and the name was given because of the analogy to miRNAs.^[3]

Function

Microproteins function as post-translational regulators.^[3] Microproteins disrupt the formation of heterodimeric, homodimeric, or multimeric complexes.^[4] Furthermore, microproteins can interact with any protein that requires functional dimers to function normally.^[3] The primary targets are transcription factors that bind to DNA as dimers.^[5][3] Microproteins regulate these complexes by creating homotypic dimers with the targets and inhibit protein complex function.^[3] The two types of miP inhibitions are: homotypic miP inhibition and heterotypic miP inhibition.^[4] In homotypic miP inhibition, microproteins interact with proteins with similar protein-protein interaction (PPI) domain.^[4] In heterotypic miP inhibition, microproteins interact with proteins with different but compatible PPI domain.^[4] In both types of inhibition, microproteins interfere and prevent the PPI domains from interacting with their normal proteins.^[4]