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HomeNatureProhormone cleavage prediction uncovers a non-incretin anti-obesity peptide

Prohormone cleavage prediction uncovers a non-incretin anti-obesity peptide

  • Philippe, J. et al. A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity. Int. J. Obes. 39, 295–302 (2015).

    Article 
    CAS 
    MATH 

    Google Scholar
     

  • Sandoval, D. A. & D’Alessio, D. A. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol. Rev. 95, 513–548 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sobrino Crespo, C., Perianes Cachero, A., Puebla Jiménez, L., Barrios, V. & Arilla Ferreiro, E. Peptides and food intake. Front. Endocrinol. 5, 58 (2014).

    Article 

    Google Scholar
     

  • Campbell, J. E. & Drucker, D. J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819–837 (2013).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Muttenthaler, M., King, G. F., Adams, D. J. & Alewood, P. F. Trends in peptide drug discovery. Nat. Rev. Drug Discov. 20, 309–325 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tatemoto, K., Carlquist, M. & Mutt, V. Neuropeptide Y–a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 296, 659–660 (1982).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, K. L., Middleditch, M. J., Williams, G. M., Brimble, M. A. & Cooper, G. J. S. Using mass spectrometry to detect, differentiate, and semiquantitate closely related peptide hormones in complex milieu: measurement of IGF-II and vesiculin. Endocrinology 156, 1194–1199 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, J. E. Neuropeptidomics: mass spectrometry-based identification and quantitation of neuropeptides. Genomics Inform. 14, 12–19 (2016).

    Article 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Fricker, L. D., Lim, J., Pan, H. & Che, F.-Y. Peptidomics: identification and quantification of endogenous peptides in neuroendocrine tissues. Mass Spectrom. Rev. 25, 327–344 (2006).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Muthusamy, B. et al. Plasma Proteome Database as a resource for proteomics research. Proteomics 5, 3531–3536 (2005).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Schwenk, J. M. et al. The Human Plasma Proteome Draft of 2017: building on the Human Plasma Peptide Atlas from mass spectrometry and complementary assays. J. Proteome Res. 16, 4299–4310 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Southey, B. R., Amare, A., Zimmerman, T. A., Rodriguez-Zas, S. L. & Sweedler, J. V. NeuroPred: a tool to predict cleavage sites in neuropeptide precursors and provide the masses of the resulting peptides. Nucleic Acids Res. 34, W267–W272 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Southey, B. R., Sweedler, J. V. & Rodriguez-Zas, S. L. A Python analytical pipeline to identify prohormone precursors and predict prohormone cleavage sites. Front. Neuroinformatics 2, 7 (2008).

    Article 
    PubMed Central 

    Google Scholar
     

  • Chance, R. E., Ellis, R. M. & Bromer, W. W. Porcine proinsulin: characterization and amino acid sequence. Science 161, 165–167 (1968).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Pollock, H. G., Hamilton, J. W., Rouse, J. B., Ebner, K. E. & Rawitch, A. B. Isolation of peptide hormones from the pancreas of the bullfrog (Rana catesbeiana). Amino acid sequences of pancreatic polypeptide, oxyntomodulin, and two glucagon-like peptides. J. Biol. Chem. 263, 9746–9751 (1988).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vecchio, I., Tornali, C., Bragazzi, N. L. & Martini, M. The discovery of insulin: an important milestone in the history of medicine. Front. Endocrinol. 9, 613 (2018).

    Article 

    Google Scholar
     

  • Tatemoto, K. & Neuropeptide, Y. Complete amino acid sequence of the brain peptide. Proc. Natl Acad. Sci. USA 79, 5485–5489 (1982).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Lovejoy, D. A. et al. Distinct sequence of gonadotropin-releasing hormone (GnRH) in dogfish brain provides insight into GnRH evolution. Proc. Natl Acad. Sci. USA 89, 6373–6377 (1992).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Steiner, D. F. The proprotein convertases. Curr. Opin. Chem. Biol. 2, 31–39 (1998).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Zheng, M., Streck, R. D., Scott, R. E., Seidah, N. G. & Pintar, J. E. The developmental expression in rat of proteases furin, PC1, PC2, and carboxypeptidase E: implications for early maturation of proteolytic processing capacity. J. Neurosci. 14, 4656–4673 (1994).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lloyd, D. J., Bohan, S. & Gekakis, N. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum. Mol. Genet. 15, 1884–1893 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Muhsin, N. I. A., Bentley, L., Bai, Y., Goldsworthy, M. & Cox, R. D. A novel mutation in the mouse Pcsk1 gene showing obesity and diabetes. Mamm. Genome 31, 17–29 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burnett, L. C. et al. Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader–Willi syndrome. J. Clin. Invest. 127, 293–305 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Lin, C. H. et al. An evaluation of liraglutide including its efficacy and safety for the treatment of obesity. Expert Opin. Pharmacother. 21, 275–285 (2020).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Kelly, A. S. et al. A randomized, controlled trial of liraglutide for adolescents with obesity. N. Engl. J. Med. 382, 2117–2128 (2020).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Peinado, J. R., Li, H., Johanning, K. & Lindberg, I. Cleavage of recombinant proenkephalin and blockade mutants by prohormone convertases 1 and 2: an in vitro specificity study. J. Neurochem. 87, 868–878 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Parvaz, N. & Jalali, Z. Molecular evolution of PCSK family: analysis of natural selection rate and gene loss. PLoS ONE 16, e0259085 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

    Article 
    PubMed 
    MATH 

    Google Scholar
     

  • Mooney, C., Haslam, N. J., Pollastri, G. & Shields, D. C. Towards the improved discovery and design of functional peptides: common features of diverse classes permit generalized prediction of bioactivity. PLoS ONE 7, e45012 (2012).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Grønning, A. G. B., Kacprowski, T. & Schéele, C. MultiPep: a hierarchical deep learning approach for multi-label classification of peptide bioactivities. Biol. Methods Protoc. 6, bpab021 (2021).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Petryszak, R. et al. Expression Atlas update—an integrated database of gene and protein expression in humans, animals and plants. Nucleic Acids Res. 44, D746–D752 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Raffin-Sanson, M. L., de Keyzer, Y. & Bertagna, X. Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. Eur. J. Endocrinol. 149, 79–90 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seizinger, B. R. et al. Isolation and structure of a novel C-terminally amidated opioid peptide, amidorphin, from bovine adrenal medulla. Nature 313, 57–59 (1985).

    Article 
    ADS 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Ghatei, M. A. et al. Distribution, molecular characterization of pituitary adenylate cyclase-activating polypeptide and its precursor encoding messenger RNA in human and rat tissues. J. Endocrinol. 136, 159–166 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Foster, S. R. et al. Discovery of human signaling systems: pairing peptides to G protein-coupled receptors. Cell 179, 895–908.e21 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Eipper, B. A., Stoffers, D. A. & Mains, R. E. The biosynthesis of neuropeptides: peptide alpha-amidation. Annu. Rev. Neurosci. 15, 57–85 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, K.-H. & Seong, B. L. Peptide amidation: production of peptide hormonesin vivo andin vitro. Biotechnol. Bioprocess Eng. 6, 244–251 (2001).

    Article 
    CAS 
    MATH 

    Google Scholar
     

  • Mukai, H., Kawai, K., Suzuki, Y., Yamashita, K. & Munekata, E. Stimulation of dog gastropancreatic hormone release by neuromedin B and its analogues. Am. J. Physiol. 252, E765–E771 (1987).

    CAS 
    PubMed 

    Google Scholar
     

  • Wettergren, A., Pridal, L., Wøjdemann, M. & Holst, J. J. Amidated and non-amidated glucagon-like peptide-1 (GLP-1): non-pancreatic effects (cephalic phase acid secretion) and stability in plasma in humans. Regul. Pept. 77, 83–87 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Milbrandt, J. Nerve growth factor rapidly induces c-fos mRNA in PC12 rat pheochromocytoma cells. Proc. Natl Acad. Sci. USA 83, 4789–4793 (1986).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Gabellini, N., Minozzi, M. C., Leon, A. & Dal Toso, R. Nerve growth factor transcriptional control of c-fos promoter transfected in cultured spinal sensory neurons. J. Cell Biol. 118, 131–138 (1992).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Berkowicz, S. R., Featherby, T. J., Whisstock, J. C. & Bird, P. I. Mice lacking Brinp2 or Brinp3, or both, exhibit behaviors consistent with neurodevelopmental disorders. Front. Behav. Neurosci. 10, 196 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wiggenhorn, A. L. et al. A class of secreted mammalian peptides with potential to expand cell-cell communication. Nat. Commun. 14, 8125 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Kim, J. T. et al. Cooperative enzymatic control of N-acyl amino acids by PM20D1 and FAAH. eLife 9, e55211 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kim, J. T., Li, V. L., Terrell, S. M., Fischer, C. R. & Long, J. Z. Family-wide annotation of enzymatic pathways by parallel in vivo metabolomics. Cell Chem. Biol. 26, 1623–1629.e3 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27–31 (2016).

    Article 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Pedersen, K.-M. et al. Optimization of pig models for translation of subcutaneous pharmacokinetics of therapeutic proteins: liraglutide, insulin aspart and insulin detemir. Transl. Res. J. Lab. Clin. Med. 239, 71–84 (2022).

    CAS 
    MATH 

    Google Scholar
     

  • Camerlink, I. & Ursinus, W. W. Tail postures and tail motion in pigs: a review. Appl. Anim. Behav. Sci. 230, 105079 (2020).

    Article 

    Google Scholar
     

  • Shaywitz, A. J. & Greenberg, M. E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem. 68, 821–861 (1999).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sheng, M., McFadden, G. & Greenberg, M. E. Membrane depolarization and calcium induce c-fos transcription via phosphorylation of transcription factor CREB. Neuron 4, 571–582 (1990).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Keen, A. C. et al. OZITX, a pertussis toxin-like protein for occluding inhibitory G protein signalling including Gαz. Commun. Biol. 5, 256 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Peng, Q., Alqahtani, S., Nasrullah, M. Z. A. & Shen, J. Functional evidence for biased inhibition of G protein signaling by YM-254890 in human coronary artery endothelial cells. Eur. J. Pharmacol. 891, 173706 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fukushima, N. et al. Melittin, a metabostatic peptide inhibiting Gs activity. Peptides 19, 811–819 (1998).

    Article 
    CAS 
    PubMed 
    MATH 

    Google Scholar
     

  • Borner, T. et al. GDF15 induces anorexia through nausea and emesis. Cell Metab. 31, 351–362.e5 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Tsai, V. W. W. et al. The anorectic actions of the TGFβ cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS ONE 9, e100370 (2014).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Madsen, C. T. et al. Combining mass spectrometry and machine learning to discover bioactive peptides. Nat. Commun. 13, 6235 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Ma, J. et al. Improved identification and analysis of small open reading frame encoded polypeptides. Anal. Chem. 88, 3967–3975 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Donohue, M. J., Filla, R. T., Steyer, D. J., Eaton, W. J. & Roper, M. G. Rapid liquid chromatography–mass spectrometry quantitation of glucose-regulating hormones from human islets of Langerhans. J. Chromatogr. A 1637, 461805 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Paxinos, G. & Franklin, K. B. J. The Mouse Brain in Stereotaxic Coordinates (Academic Press, 2001).

  • Allen, W. E. et al. Thirst-associated preoptic neurons encode an aversive motivational drive. Science 357, 1149–1155 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Park, Y.-G. et al. Protection of tissue physicochemical properties using polyfunctional crosslinkers. Nat. Biotechnol. 37, 73–83 (2019).

    Article 
    CAS 
    MATH 

    Google Scholar
     

  • Kim, S.-Y. et al. Stochastic electrotransport selectively enhances the transport of highly electromobile molecules. Proc. Natl Acad. Sci. USA 112, E6274–E6283 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shelhamer, E., Long, J. & Darrel, T. Fully convolutional networks for semantic segmentation. Preprint at https://doi.org/10.48550/arXiv.1605.06211 (2016).

  • Ronneberger, O., Fischer, P. & Brox, T. U-Net: convolutional networks for biomedical image segmentation. Preprint at https://doi.org/10.48550/arXiv.1505.04597 (2015).

  • Murray, E. et al. Simple, scalable proteomic imaging for high-dimensional profiling of intact systems. Cell 163, 1500–1514 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 
    MATH 

    Google Scholar
     

  • Batra, V. R. & Schrott, L. M. Acute oxycodone induces the pro-emetic pica response in rats. J. Pharmacol. Exp. Ther. 339, 738–745 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

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