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In many species, taste receptors have shown loss of functions. The evolutionary process of which taste receptors lost their function is believed to be adaptive evolution where it is associated with feeding ecology to drive specialization and bifurcation of taste receptors. <ref name=":0">{{Cite journal|last=Feng|first=Ping|last2=Zhao|first2=HuaBin|date=2013-6|title=Complex evolutionary history of the vertebrate sweet/umami taste receptor genes|url=http://link.springer.com/10.1007/s11434-013-5811-5|journal=Chinese Science Bulletin|language=en|volume=58|issue=18|pages=2198–2204|doi=10.1007/s11434-013-5811-5|issn=1001-6538}}</ref> Out of all the taste receptors, bitter, sweet, and umami are shown to have a correlation between inactivation of taste receptors and feeding behavior. <ref name=":0" /> However, there are no strong evidences that support any vertebrates are missing the bitter taste receptor genes. <ref name=":0" />
A '''microprotein''' (miP) is a small [[protein]] of about 100–150 amino acids or fewer encoded from a [[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><ref name=":4">{{Cite journal |last=Jaunbocus |first=Nadiya |last2=Ebenki |first2=Valerie |last3=Su |first3=Haomiao |last4=Slavoff |first4=Sarah A. |date=2025-06-20 |title=Eukaryotic Microproteins |url=https://www.annualreviews.org/content/journals/10.1146/annurev-biochem-080124-012840 |journal=Annual Review of Biochemistry |language=en |volume=94 |issue=1 |pages=1–28 |doi=10.1146/annurev-biochem-080124-012840 |issn=0066-4154 |pmc=12207985 |pmid=40245354}}</ref> also known as '''sORF-encoded protein''' ('''SEP'''). They are a class of protein with a single [[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 [[MicroRNA|microRNAs]] (miRNAs) and [[Protein dimer|heterodimerize]] 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" /> There are several methods for microprotein study, such as ribosome profiling, mass spectrometry, and genetic screening.<ref name=":4" /> In humans, they are associated with genetic diseases and cancers, and are called [[Peptidein|peptideins]].<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|url-access=subscription}}</ref>


== History ==
The first miP was discovered during a research in the early 1990s on genes for [[Basic helix-loop-helix|basic helix–loop–helix]] (bHLH) [[Transcription factor|transcription factors]] from a [[Murinae|murine]] [[Acute erythroid leukemia|erythroleukaemia]] cell [[cDNA library]].<ref name=":1" /> The protein was an [[Inhibitor of DNA-binding protein|inhibitor of DNA binding]] (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 sweet taste receptor is one of the taste receptors where the function has been lost. In mammals, the predominant sweet taste receptor is the Type 1 taste receptor Tas1r2/Tas1r3. <ref name=":1">{{Cite journal|last=Jiang|first=P.|last2=Josue|first2=J.|last3=Li|first3=X.|last4=Glaser|first4=D.|last5=Li|first5=W.|last6=Brand|first6=J. G.|last7=Margolskee|first7=R. F.|last8=Reed|first8=D. R.|last9=Beauchamp|first9=G. K.|date=2012-03-27|title=Major taste loss in carnivorous mammals|url=http://www.pnas.org/cgi/doi/10.1073/pnas.1118360109|journal=Proceedings of the National Academy of Sciences|language=en|volume=109|issue=13|pages=4956–4961|doi=10.1073/pnas.1118360109|issn=0027-8424|pmc=PMC3324019|pmid=22411809}}</ref> Some mammalian species such as cats and vampire bats have shown inability to taste sweet. <ref name=":1" />  In these species, the cause of loss of function of the sweet receptor is due to the pseudogenization of Tas1r2. <ref name=":1" /> The pseudogenization of Tas1r2 is also observed in non-mammalian species such as chickens and tongueless Western clawed frog, and these species also show the inability to taste sweet. <ref name=":1" /> The pseudogenization of Tas1r2 is widespread and independent in the order Carnivora. <ref name=":1" /> Many studies have shown that the pseduogenization of taste receptors is caused by a deleterious mutation in the open reading frames (ORF). <ref name=":2">{{Cite journal|last=Antinucci|first=Marco|last2=Risso|first2=Davide|date=2017-11-28|title=A Matter of Taste: Lineage-Specific Loss of Function of Taste Receptor Genes in Vertebrates|url=http://journal.frontiersin.org/article/10.3389/fmolb.2017.00081/full|journal=Frontiers in Molecular Biosciences|volume=4|doi=10.3389/fmolb.2017.00081|issn=2296-889X|pmc=PMC5712339|pmid=29234667}}</ref> In a study, it was found that in nonfeline carnivorous species, these species showed ORF-disrupting mutations of Tas1r2, and they occurred independently among the species. <ref name=":1" /> They also showed high variance in their lineages. <ref name=":1" /> It is hypothesized that the pseudogenization of Tas1r2 occurred through convergent evolution where carnivorous species lost their ability to taste sweet because of dietary behavior. <ref name=":1" /> Overall, the loss of function of the a taste receptor is a evolutionary process that occurred due to a dietary change in species. <ref name=":2" />
The first plant microprotein discovered was the LITTLE ZIPPER (ZPR) protein.<ref name=":0" /> The LITTLE ZIPPER protein contains a [[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]] 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" />


Umami is also a taste receptor where the function has been lost in many species. The predominant umami taste receptors are Tas1r1/Tas1r3. <ref name=":1" /> In two lineages of aquatic mammals including dolphins and sea lions, Tas1r1 has been found to be pseudogenized. <ref name=":1" /> The pseudogenization of Tas1r1 has also been found in terrestrial, carnivorous species. <ref name=":1" /> While the panda belongs to the order Carnivora, it is herbivorous where 99% of its diet is bamboo, and it cannot taste umami. <ref name=":3" /> Genome sequence of the panda shows that its Tas1r1 gene is pseudogenized. <ref name=":3">{{Cite journal|last=Zhao|first=H.|last2=Yang|first2=J.-R.|last3=Xu|first3=H.|last4=Zhang|first4=J.|date=2010-12-01|title=Pseudogenization of the Umami Taste Receptor Gene Tas1r1 in the Giant Panda Coincided with its Dietary Switch to Bamboo|url=https://academic.oup.com/mbe/article-lookup/doi/10.1093/molbev/msq153|journal=Molecular Biology and Evolution|language=en|volume=27|issue=12|pages=2669–2673|doi=10.1093/molbev/msq153|issn=0737-4038|pmc=PMC3108379|pmid=20573776}}</ref> In a study, it was found that in all species in the order Carnivora except the panda, the open reading frame was maintained. In panda, the nonsynonymous to synonymous substitutions ratio was found to be much higher than other species in order Carnivora. <ref name=":1" /> This data correlates with fossil records date of the panda to show where panda switched from carnivore to herbivore diet. <ref name=":1" /> Therefore, the loss of function of umami in panda is hypothesized to be caused by dietary change where the panda became less dependence on meat. <ref name=":1" /> However, these studies do not explain herbivores such as horses and cows that have retained the Tas1r1 receptor. <ref name=":3" />
== 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 regulation|post-translational regulators]].<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" /> Microproteins plays roles in biological process such as immunity and inflammation, cancer and cell cycle regulation, cellular transport, muscle and heart functions, gene expression and genome maintenance, proteostasis, and metabolic homeostasis.<ref name=":4" />  
 
== References ==
<references />
 
[[Category:Protein classification]]

Latest revision as of 03:36, 1 October 2026

A microprotein (miP) is a small protein of about 100–150 amino acids or fewer encoded from a small open reading frame (sORF),[1][2] also known as sORF-encoded protein (SEP). They are a class of protein with a single protein domain. They are related to multidomain proteins.[3] Microproteins regulate larger multidomain proteins at the post-translational level.[4] Microproteins are analogous to microRNAs (miRNAs) and heterodimerize with their targets causing dominant and negative effects.[5] In animals and plants, microproteins influence many biological processes.[3] Because of their dominant effects on their targets, microproteins are currently under study for use in biotechnology.[3] There are several methods for microprotein study, such as ribosome profiling, mass spectrometry, and genetic screening.[2] In humans, they are associated with genetic diseases and cancers, and are called peptideins.[6]

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.[4] The protein was an inhibitor of DNA binding (ID protein), and negatively regulated the transcription factor complex.[4] The protein was 16 kDa and consisted of a helix-loop-helix (HLH) domain.[3] The microprotein formed bHLH/HLH heterodimers that disrupted the functional basic helix–loop–helix (bHLH) homodimers.[3]

The first plant microprotein discovered was the LITTLE ZIPPER (ZPR) protein.[3] The LITTLE ZIPPER protein contains a leucine zipper domain, but lacks the domains required for DNA binding and transcription activation.[3] Thus, LITTLE ZIPPER protein is analogous to the ID protein.[3] 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.[4]

The ID protein or proteins similar to ID are found in all animals.[4] Plant microproteins are only found in higher orders.[4] 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.[4]

Structure

Microproteins generally feature a single protein domain.[3][5] The active form is translated from smORF.[1] smORFs can be less than 100 codons.[1] However, not all microproteins are small, and the name was given because of the analogy to miRNAs.[4] 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.[7] 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.[8] 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.[9]

Function

Microproteins function as post-translational regulators.[4] Microproteins disrupt the formation of heterodimeric, homodimeric, or multimeric complexes.[5] Furthermore, microproteins can interact with any protein that requires functional dimers to function normally.[4] The primary targets are transcription factors that bind to DNA as dimers.[10][4] Microproteins regulate these complexes by creating homotypic dimers with the targets and inhibit protein complex function.[4] The two types of miP inhibitions are: homotypic miP inhibition and heterotypic miP inhibition.[5] In homotypic miP inhibition, microproteins interact with proteins with similar protein-protein interaction (PPI) domain.[5] In heterotypic miP inhibition, microproteins interact with proteins with different but compatible PPI domain.[5] In both types of inhibition, microproteins interfere and prevent the PPI domains from interacting with their normal proteins.[5] Microproteins plays roles in biological process such as immunity and inflammation, cancer and cell cycle regulation, cellular transport, muscle and heart functions, gene expression and genome maintenance, proteostasis, and metabolic homeostasis.[2]

References

  1. ↑ 1.0 1.1 1.2 "The Dark Matter of the Human Proteome" (in en). https://www.the-scientist.com/features/the-dark-matter-of-the-human-proteome-65628. 
  2. ↑ 2.0 2.1 2.2 Jaunbocus, Nadiya; Ebenki, Valerie; Su, Haomiao; Slavoff, Sarah A. (2025-06-20). "Eukaryotic Microproteins" (in en). Annual Review of Biochemistry 94 (1): 1–28. doi:10.1146/annurev-biochem-080124-012840. ISSN 0066-4154. PMID 40245354. PMC: 12207985. https://www.annualreviews.org/content/journals/10.1146/annurev-biochem-080124-012840. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Bhati, Kaushal Kumar; Blaakmeer, Anko; Paredes, Esther Botterweg; Dolde, Ulla; Eguen, Tenai; Hong, Shin-Young; Rodrigues, Vandasue; Straub, Daniel; et al. (2018-04-18). "Approaches to identify and characterize microProteins and their potential uses in biotechnology". Cellular and Molecular Life Sciences 75 (14): 2529–2536. doi:10.1007/s00018-018-2818-8. ISSN 1420-682X. PMID 29670998. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 Staudt, Annica-Carolin; Wenkel, Stephan (2010-12-10). "Regulation of protein function by 'microProteins'". EMBO Reports 12 (1): 35–42. doi:10.1038/embor.2010.196. ISSN 1469-221X. PMID 21151039. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Eguen, T; Straub, D; Graeff, M; Wenkel, S (August 2015). "MicroProteins: small size-big impact". Trends in Plant Science 20 (8): 477–482. doi:10.1016/j.tplants.2015.05.011. PMID 26115780. Bibcode: 2015TPS....20..477E. 
  6. ↑ Callaway, Ewen (2026-05-06). "Revealed: the mysterious ‘dark’ proteins that might play a big role in biology" (in en). Nature. doi:10.1038/d41586-026-01492-x. ISSN 1476-4687. https://www.nature.com/articles/d41586-026-01492-x. 
  7. ↑ Mohsen, Jessica J.; Martel, Alina A.; Slavoff, Sarah A. (December 2023). "Microproteins-Discovery, structure, and function" (in en). Proteomics 23 (23–24). doi:10.1002/pmic.202100211. PMID 37603371. 
  8. ↑ Thambu, Kishan; Glomb, Victoria; Hernandez Trapero, Rolando; Facelli, Julio C. (2022). "Microproteins: a 3D protein structure prediction analysis" (in en). Journal of Biomolecular Structure and Dynamics 40 (24): 13738–13746. doi:10.1080/07391102.2021.1993343. PMID 34705603. 
  9. ↑ Eicholt, Lars A. (2026). "Structure and Disorder Predictions of Microproteins: Usage, Applications, and Pitfalls". in Wenkel, Stephan (in en). Microproteins: Methods and Protocols. Methods in Molecular Biology. 2992. New York, NY: Humana. pp. 129–150. doi:10.1007/978-1-0716-5013-4_10. ISBN 978-1-0716-5012-7. 
  10. ↑ de Klein, Niek; Magnani, Enrico; Banf, Michael; Rhee, Seung Yon (2015). "microProtein Prediction Program (miP3): A Software for Predicting microProteins and Their Target Transcription Factors". International Journal of Genomics 2015. doi:10.1155/2015/734147. ISSN 2314-436X. PMID 26060811. 
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