# Microprotein

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> Source: https://en.wikipedia.org/wiki/Microprotein
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{{for|a similar (if not identical) concept|Micropeptide}}
A '''microprotein''' (miP) is a small [protein](/source/protein) encoded from a [small open reading frame](/source/small_open_reading_frame) (sORF),<ref name=":3">{{Cite web|url=https://www.the-scientist.com/features/the-dark-matter-of-the-human-proteome-65628|title=The Dark Matter of the Human Proteome|website=The Scientist Magazine®|language=en|access-date=2019-04-25}}</ref> also known as '''sORF-encoded protein''' ('''SEP'''). They are a class of protein with a single [protein domain](/source/protein_domain). They are related to multidomain proteins.<ref name=":0">{{Cite journal|last1=Bhati|first1=Kaushal Kumar|last2=Blaakmeer|first2=Anko|last3=Paredes|first3=Esther Botterweg|last4=Dolde|first4=Ulla|last5=Eguen|first5=Tenai|last6=Hong|first6=Shin-Young|last7=Rodrigues|first7=Vandasue|last8=Straub|first8=Daniel|last9=Sun|first9=Bin|date=2018-04-18|title=Approaches to identify and characterize microProteins and their potential uses in biotechnology|journal=Cellular and Molecular Life Sciences|volume=75|issue=14|pages=2529–2536|doi=10.1007/s00018-018-2818-8|pmid=29670998|pmc=6003976|issn=1420-682X}}</ref> Microproteins regulate larger multidomain proteins at the post-translational level.<ref name=":1">{{Cite journal|last1=Staudt|first1=Annica-Carolin|last2=Wenkel|first2=Stephan|date=2010-12-10|title=Regulation of protein function by 'microProteins'|journal=EMBO Reports|volume=12|issue=1|pages=35–42|doi=10.1038/embor.2010.196|pmid=21151039|pmc=3024132|issn=1469-221X}}</ref> Microproteins are analogous to [microRNAs](/source/MicroRNA) (miRNAs) and [heterodimerize](/source/Protein_dimer) with their targets causing dominant and negative effects.<ref name=":2">{{Cite journal|last1=Eguen|first1=T|last2=Straub|first2=D|last3=Graeff|first3=M|last4=Wenkel|first4=S|date=August 2015|title=MicroProteins: small size-big impact|journal=Trends in Plant Science|volume=20|issue=8|pages=477–482|doi=10.1016/j.tplants.2015.05.011|pmid=26115780|bibcode=2015TPS....20..477E}}</ref> In animals and plants, microproteins influence many biological processes.<ref name=":0" /> Because of their dominant effects on their targets, microproteins are currently under study for use in biotechnology.<ref name=":0" /> In humans, they are associated with genetic diseases and cancers, and are called [peptideins](/source/Peptidein).<ref name=":02">{{Cite journal |last=Callaway|first=Ewen|date=2026-05-06|title=Revealed: the mysterious ‘dark’ proteins that might play a big role in biology|url=https://www.nature.com/articles/d41586-026-01492-x|journal=Nature|language=en|doi=10.1038/d41586-026-01492-x|issn=1476-4687}}</ref>

== History ==
The first miP was discovered during a research in the early 1990s on genes for [basic helix–loop–helix](/source/Basic_helix-loop-helix) (bHLH) [transcription factors](/source/Transcription_factor) from a [murine](/source/Murinae) [erythroleukaemia](/source/Acute_erythroid_leukemia) cell [cDNA library](/source/cDNA_library).<ref name=":1" /> The protein was an [inhibitor of DNA binding](/source/Inhibitor_of_DNA-binding_protein) (ID protein), and negatively regulated the transcription factor complex.<ref name=":1" /> The protein was 16 kDa and consisted of a helix-loop-helix (HLH) domain.<ref name=":0" /> The microprotein formed bHLH/HLH heterodimers that disrupted the functional basic helix–loop–helix (bHLH) homodimers.<ref name=":0" /> 

The first plant microprotein discovered was the LITTLE ZIPPER (ZPR) protein.<ref name=":0" /> The LITTLE ZIPPER protein contains a [leucine zipper](/source/leucine_zipper) domain, but lacks the domains required for DNA binding and transcription activation.<ref name=":0" /> Thus, LITTLE ZIPPER protein is analogous to the ID protein.<ref name=":0" /> 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.<ref name=":1" /> 

The ID protein or proteins similar to ID are found in all animals.<ref name=":1" /> Plant microproteins are only found in higher orders.<ref name=":1" /> However, the [homeodomain](/source/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.<ref name=":1" />

== Structure ==
Microproteins generally feature a single protein domain.<ref name=":0" /><ref name=":2" /> The active form is translated from smORF.<ref name=":3" /> smORFs can be less than 100 codons.<ref name=":3" /> However, not all microproteins are small, and the name was given because of the analogy to miRNAs.<ref name=":1" />
Despite their short length, microproteins have been shown to a limited but diverse set of structural folds (including predominantly α-helical and transmembrane-helical structures), but many candidates also show substantial intrinsic disorder; experimentally determined microprotein structures have been solved using approaches including X-ray crystallography, cryo-electron microscopy, and NMR.<ref name="Mohsen2023">{{Cite journal |last1=Mohsen |first1=Jessica J. |last2=Martel |first2=Alina A. |last3=Slavoff |first3=Sarah A. |date=December 2023 |title=Microproteins-Discovery, structure, and function |journal=Proteomics |volume=23 |issue=23–24 |article-number=e2100211 |doi=10.1002/pmic.202100211 |pmid=37603371 |pmc=10841188 |language=en}}</ref> A computational survey of predicted structures for 44 microproteins reported broadly similar structural characteristics across the set and comparatively few predicted small-molecule ligand-binding sites.<ref name="Thambu2022">{{Cite journal |last1=Thambu |first1=Kishan |last2=Glomb |first2=Victoria |last3=Hernandez Trapero |first3=Rolando |last4=Facelli |first4=Julio C. |date=2022 |title=Microproteins: a 3D protein structure prediction analysis |journal=Journal of Biomolecular Structure and Dynamics |volume=40 |issue=24 |pages=13738–13746 |doi=10.1080/07391102.2021.1993343 |pmid=34705603 |pmc=9489054 |language=en}}</ref> Because many structure/disorder predictors are trained primarily on longer “classical” proteins, dedicated workflows and precautions have been proposed for reliable structure and disorder prediction for microproteins.<ref name="Eicholt2026">{{Cite book |last=Eicholt |first=Lars A. |date=2026 |chapter=Structure and Disorder Predictions of Microproteins: Usage, Applications, and Pitfalls |title=Microproteins: Methods and Protocols |editor-last=Wenkel |editor-first=Stephan |series=Methods in Molecular Biology |volume=2992 |pages=129–150 |publisher=Humana |location=New York, NY |doi=10.1007/978-1-0716-5013-4_10 |pmid=41241904 |isbn=978-1-0716-5012-7 |language=en}}</ref>

== Function ==
Microproteins function as [post-translational regulators](/source/Post-translational_regulation).<ref name=":1" /> Microproteins disrupt the formation of heterodimeric, homodimeric, or multimeric complexes.<ref name=":2" /> Furthermore, microproteins can interact with any protein that requires functional dimers to function normally.<ref name=":1" /> The primary targets are transcription factors that bind to DNA as dimers.<ref>{{Cite journal|last1=de Klein|first1=Niek|last2=Magnani|first2=Enrico|last3=Banf|first3=Michael|last4=Rhee|first4=Seung Yon|date=2015|title=microProtein Prediction Program (miP3): A Software for Predicting microProteins and Their Target Transcription Factors|journal=International Journal of Genomics|volume=2015|article-number=734147|doi=10.1155/2015/734147|pmid=26060811|pmc=4427850|issn=2314-436X|doi-access=free}}</ref><ref name=":1" /> Microproteins regulate these complexes by creating homotypic dimers with the targets and inhibit protein complex function.<ref name=":1" /> The two types of miP inhibitions are: homotypic miP inhibition and heterotypic miP inhibition.<ref name=":2" /> In homotypic miP inhibition, microproteins interact with proteins with similar protein-protein interaction (PPI) domain.<ref name=":2" /> In heterotypic miP inhibition, microproteins interact with proteins with different but compatible PPI domain.<ref name=":2" /> In both types of inhibition, microproteins interfere and prevent the PPI domains from interacting with their normal proteins.<ref name=":2" /> 

== References ==
<references />

Category:Protein classification
Category:Post-translational modification

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Adapted from the Wikipedia article [Microprotein](https://en.wikipedia.org/wiki/Microprotein) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Microprotein?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.