{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:29:17Z","timestamp":1790400557364,"version":"4.1.0"},"reference-count":78,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T00:00:00Z","timestamp":1701216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The N-end rule pathway is a proteolytic system involving the destabilization of N-terminal amino acids, known as N-degrons, which are recognized by N-recognins. Dysregulation of the N-end rule pathway results in the accumulation of undesired proteins, causing various diseases. The E3 ligases of the UBR subfamily recognize and degrade N-degrons through the ubiquitin-proteasome system. Herein, we investigated UBR4, which has a distinct mechanism for recognizing type-2 N-degrons. Structural analysis revealed that the UBR box of UBR4 differs from other UBR boxes in the N-degron binding sites. It recognizes type-2 N-terminal amino acids containing an aromatic ring and type-1 N-terminal arginine through two phenylalanines on its hydrophobic surface. We also characterized the binding mechanism for the second ligand residue. This is the report on the structural basis underlying the recognition of type-2 N-degrons by the UBR box with implications for understanding the N-end rule pathway.<\/jats:p>","DOI":"10.1038\/s42003-023-05602-7","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T12:02:04Z","timestamp":1701259324000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Insights into the recognition mechanism in the UBR box of UBR4 for its specific substrates"],"prefix":"10.1038","volume":"6","author":[{"given":"Da Eun","family":"Jeong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Seon","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1784-8975","authenticated-orcid":false,"given":"Bonsu","family":"Ku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3019-0699","authenticated-orcid":false,"given":"Cheol-Hee","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0293-6972","authenticated-orcid":false,"given":"Seung Jun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7878-0367","authenticated-orcid":false,"given":"Ho-Chul","family":"Shin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,29]]},"reference":[{"key":"5602_CR1","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1146\/annurev-biochem-051710-093308","volume":"81","author":"T Tasaki","year":"2012","unstructured":"Tasaki, T., Sriram, S. M., Park, K. S. & Kwon, Y. T. The N-end rule pathway. Annu. Rev. Biochem. 81, 261\u2013289 (2012).","journal-title":"Annu. Rev. Biochem."},{"key":"5602_CR2","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1016\/j.tcb.2014.05.001","volume":"24","author":"DJ Gibbs","year":"2014","unstructured":"Gibbs, D. J., Bacardit, J., Bachmair, A. & Holdsworth, M. J. The eukaryotic N-end rule pathway: conserved mechanisms and diverse functions. Trends Cell Biol. 24, 603\u2013611 (2014).","journal-title":"Trends Cell Biol."},{"key":"5602_CR3","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1002\/pro.666","volume":"20","author":"A Varshavsky","year":"2011","unstructured":"Varshavsky, A. The N-end rule pathway and regulation by proteolysis. Protein Sci. 20, 1298\u20131345 (2011).","journal-title":"Protein Sci."},{"key":"5602_CR4","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1046\/j.1365-2443.1997.1020301.x","volume":"2","author":"A Varshavsky","year":"1997","unstructured":"Varshavsky, A. The N-end rule pathway of protein degradation. Genes Cells 2, 13\u201328 (1997).","journal-title":"Genes Cells"},{"key":"5602_CR5","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1038\/nsmb1010-1164","volume":"17","author":"SM Sriram","year":"2010","unstructured":"Sriram, S. M. & Kwon, Y. T. The molecular principles of N-end rule recognition. Nat. Struct. Mol. Biol. 17, 1164\u20131165 (2010).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"5602_CR6","doi-asserted-by":"publisher","first-page":"E1839","DOI":"10.1073\/pnas.1207786109","volume":"109","author":"KI Piatkov","year":"2012","unstructured":"Piatkov, K. I., Brower, C. S. & Varshavsky, A. The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments. Proc. Natl Acad. Sci. USA 109, E1839\u2013E1847 (2012).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5602_CR7","doi-asserted-by":"publisher","first-page":"3414","DOI":"10.3390\/ijms19113414","volume":"19","author":"MA Eldeeb","year":"2018","unstructured":"Eldeeb, M. A., Fahlman, R. P., Esmaili, M. & Ragheb, M. A. Regulating apoptosis by degradation: the N-end rule-mediated regulation of apoptotic proteolytic fragments in mammalian cells. Int. J. Mol. Sci. 19, 3414 (2018).","journal-title":"Int. J. Mol. Sci."},{"key":"5602_CR8","doi-asserted-by":"crossref","unstructured":"Wang, Z. et al. A picorna-like virus suppresses the N-end rule pathway to inhibit apoptosis. eLife 6, e30590 (2017).","DOI":"10.7554\/eLife.30590"},{"key":"5602_CR9","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1038\/cdd.2014.115","volume":"21","author":"Q Huang","year":"2014","unstructured":"Huang, Q. et al. Ubr3 E3 ligase regulates apoptosis by controlling the activity of DIAP1 in Drosophila. Cell Death Differ. 21, 1961\u20131970 (2014).","journal-title":"Cell Death Differ."},{"key":"5602_CR10","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.4161\/auto.24643","volume":"9","author":"ST Kim","year":"2013","unstructured":"Kim, S. T. et al. The N-end rule proteolytic system in autophagy. Autophagy 9, 1100\u20131103 (2013).","journal-title":"Autophagy"},{"key":"5602_CR11","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1080\/15548627.2017.1415190","volume":"14","author":"H Cha-Molstad","year":"2018","unstructured":"Cha-Molstad, H. et al. Regulation of autophagic proteolysis by the N-recognin SQSTM1\/p62 of the N-end rule pathway. Autophagy 14, 359\u2013361 (2018).","journal-title":"Autophagy"},{"key":"5602_CR12","doi-asserted-by":"publisher","first-page":"E2716","DOI":"10.1073\/pnas.1719110115","volume":"115","author":"YD Yoo","year":"2018","unstructured":"Yoo, Y. D. et al. N-terminal arginylation generates a bimodal degron that modulates autophagic proteolysis. Proc. Natl Acad. Sci. USA 115, E2716\u2013E2724 (2018).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5602_CR13","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1111\/nph.15387","volume":"221","author":"J Vicente","year":"2019","unstructured":"Vicente, J. et al. Distinct branches of the N-end rule pathway modulate the plant immune response. New Phytol. 221, 988\u20131000 (2019).","journal-title":"New Phytol."},{"key":"5602_CR14","doi-asserted-by":"publisher","first-page":"e0176204","DOI":"10.1371\/journal.pone.0176204","volume":"12","author":"E Jentho","year":"2017","unstructured":"Jentho, E. et al. microRNA-125a-3p is regulated by MyD88 in Legionella pneumophila infection and targets NTAN1. PLoS ONE 12, e0176204 (2017).","journal-title":"PLoS ONE"},{"key":"5602_CR15","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1126\/science.aau1208","volume":"364","author":"AJ Chui","year":"2019","unstructured":"Chui, A. J. et al. N-terminal degradation activates the NLRP1B inflammasome. Science 364, 82\u201385 (2019).","journal-title":"Science"},{"key":"5602_CR16","doi-asserted-by":"publisher","first-page":"903","DOI":"10.3390\/biom10060903","volume":"10","author":"D Leboeuf","year":"2020","unstructured":"Leboeuf, D., Pyatkov, M., Zatsepin, T. S. & Piatkov, K. The Arg\/N-degron pathway-a potential running back in fine-tuning the inflammatory response? Biomolecules 10, 903 (2020).","journal-title":"Biomolecules"},{"key":"5602_CR17","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1016\/j.ymthe.2020.01.021","volume":"28","author":"D Leboeuf","year":"2020","unstructured":"Leboeuf, D. et al. Downregulation of the Arg\/N-degron pathway sensitizes cancer cells to chemotherapy in vivo. Mol. Ther. 28, 1092\u20131104 (2020).","journal-title":"Mol. Ther."},{"key":"5602_CR18","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1038\/s41589-018-0036-1","volume":"14","author":"C Dong","year":"2018","unstructured":"Dong, C. et al. Molecular basis of GID4-mediated recognition of degrons for the Pro\/N-end rule pathway. Nat. Chem. Biol. 14, 466\u2013473 (2018).","journal-title":"Nat. Chem. Biol."},{"key":"5602_CR19","doi-asserted-by":"publisher","first-page":"7495","DOI":"10.1074\/jbc.M111.301002","volume":"287","author":"Z Xu","year":"2012","unstructured":"Xu, Z., Payoe, R. & Fahlman, R. P. The C-terminal proteolytic fragment of the breast cancer susceptibility type 1 protein (BRCA1) is degraded by the N-end rule pathway. J. Biol.Chem. 287, 7495\u20137502 (2012).","journal-title":"J. Biol.Chem."},{"key":"5602_CR20","doi-asserted-by":"publisher","first-page":"e1008863","DOI":"10.1371\/journal.pgen.1008863","volume":"16","author":"Z Sheng","year":"2020","unstructured":"Sheng, Z. & Du, W. NatB regulates Rb mutant cell death and tumor growth by modulating EGFR\/MAPK signaling through the N-end rule pathways. PLoS Genet. 16, e1008863 (2020).","journal-title":"PLoS Genet."},{"key":"5602_CR21","doi-asserted-by":"publisher","first-page":"41300","DOI":"10.1074\/jbc.M110.169136","volume":"285","author":"B Kumar","year":"2010","unstructured":"Kumar, B., Lecompte, K. G., Klein, J. M. & Haas, A. L. Ser(120) of Ubc2\/Rad6 regulates ubiquitin-dependent N-end rule targeting by E3alpha\/Ubr1. J. Biol. Chem. 285, 41300\u201341309 (2010).","journal-title":"J. Biol. Chem."},{"key":"5602_CR22","doi-asserted-by":"publisher","first-page":"bqaa185","DOI":"10.1210\/endocr\/bqaa185","volume":"161","author":"MA Eldeeb","year":"2020","unstructured":"Eldeeb, M. A., Zorca, C. E. & Fahlman, R. P. Targeting cancer cells via N-degron-based PROTACs. Endocrinology 161, bqaa185 (2020).","journal-title":"Endocrinology"},{"key":"5602_CR23","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1007\/s12640-021-00396-0","volume":"40","author":"MA Eldeeb","year":"2022","unstructured":"Eldeeb, M. A., Ragheb, M. A., Soliman, M. H. & Fahlman, R. P. Regulation of neurodegeneration-associated protein fragments by the N-degron pathways. Neurotox. Res. 40, 298\u2013318 (2022).","journal-title":"Neurotox. Res."},{"key":"5602_CR24","doi-asserted-by":"publisher","first-page":"jcs231662","DOI":"10.1242\/jcs.231662","volume":"132","author":"A Tran","year":"2019","unstructured":"Tran, A. The N-end rule pathway and Ubr1 enforce protein compartmentalization via P2-encoded cellular location signals. J. Cell Sci. 132, jcs231662 (2019).","journal-title":"J. Cell Sci."},{"key":"5602_CR25","doi-asserted-by":"publisher","first-page":"962","DOI":"10.1111\/j.1471-4159.2004.02376.x","volume":"89","author":"MD Kaytor","year":"2004","unstructured":"Kaytor, M. D., Wilkinson, K. D. & Warren, S. T. Modulating huntingtin half-life alters polyglutamine-dependent aggregate formation and cell toxicity. J. Neurochem. 89, 962\u2013973 (2004).","journal-title":"J. Neurochem."},{"key":"5602_CR26","doi-asserted-by":"publisher","first-page":"6863","DOI":"10.3748\/wjg.14.6863","volume":"14","author":"N Alkhouri","year":"2008","unstructured":"Alkhouri, N. et al. Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing. World J. Gastroenterol. 14, 6863\u20136866 (2008).","journal-title":"World J. Gastroenterol."},{"key":"5602_CR27","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1002\/mgg3.319","volume":"5","author":"M Sukalo","year":"2017","unstructured":"Sukalo, M. et al. Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis. Mol. Genet. Genomic. Med. 5, 774\u2013780 (2017).","journal-title":"Mol. Genet. Genomic. Med."},{"key":"5602_CR28","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1038\/ng1681","volume":"37","author":"M Zenker","year":"2005","unstructured":"Zenker, M. et al. Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome). Nat. Genet. 37, 1345\u20131350 (2005).","journal-title":"Nat. Genet."},{"key":"5602_CR29","doi-asserted-by":"publisher","first-page":"e24925","DOI":"10.1371\/journal.pone.0024925","volume":"6","author":"CS Hwang","year":"2011","unstructured":"Hwang, C. S. et al. Ubiquitin ligases of the N-end rule pathway: assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome. PLoS ONE 6, e24925 (2011).","journal-title":"PLoS ONE"},{"key":"5602_CR30","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1002\/humu.22538","volume":"35","author":"M Sukalo","year":"2014","unstructured":"Sukalo, M. et al. Mutations in the human UBR1 gene and the associated phenotypic spectrum. Hum. Mutat. 35, 521\u2013531 (2014).","journal-title":"Hum. Mutat."},{"key":"5602_CR31","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1038\/nrm3217","volume":"12","author":"SM Sriram","year":"2011","unstructured":"Sriram, S. M., Kim, B. Y. & Kwon, Y. T. The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat. Rev. Mol. Cell Biol. 12, 735\u2013747 (2011).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"5602_CR32","doi-asserted-by":"publisher","first-page":"6134","DOI":"10.18632\/aging.102177","volume":"11","author":"OI Kechko","year":"2019","unstructured":"Kechko, O. I. et al. Beta-amyloid induces apoptosis of neuronal cells by inhibition of the Arg\/N-end rule pathway proteolytic activity. Aging (Albany NY) 11, 6134\u20136152 (2019).","journal-title":"Aging (Albany NY)"},{"key":"5602_CR33","doi-asserted-by":"publisher","first-page":"8323","DOI":"10.3390\/ijms22158323","volume":"22","author":"JG Kim","year":"2021","unstructured":"Kim, J. G. et al. Signaling pathways regulated by UBR box-containing E3 ligases. Int. J. Mol. Sci. 22, 8323 (2021).","journal-title":"Int. J. Mol. Sci."},{"key":"5602_CR34","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/nrd3321","volume":"10","author":"L Bedford","year":"2011","unstructured":"Bedford, L., Lowe, J., Dick, L. R., Mayer, R. J. & Brownell, J. E. Ubiquitin-like protein conjugation and the ubiquitin-proteasome system as drug targets. Nat. Rev. Drug Discov. 10, 29\u201346 (2011).","journal-title":"Nat. Rev. Drug Discov."},{"key":"5602_CR35","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1016\/j.tcb.2013.12.003","volume":"24","author":"G Kleiger","year":"2014","unstructured":"Kleiger, G. & Mayor, T. Perilous journey: a tour of the ubiquitin-proteasome system. Trends Cell Biol. 24, 352\u2013359 (2014).","journal-title":"Trends Cell Biol."},{"key":"5602_CR36","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.1002\/med.21675","volume":"40","author":"MD Asmamaw","year":"2020","unstructured":"Asmamaw, M. D., Liu, Y., Zheng, Y. C., Shi, X. J. & Liu, H. M. Skp2 in the ubiquitin-proteasome system: a comprehensive review. Med. Res. Rev. 40, 1920\u20131949 (2020).","journal-title":"Med. Res. Rev."},{"key":"5602_CR37","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.ddtec.2017.11.006","volume":"26","author":"Y Leestemaker","year":"2017","unstructured":"Leestemaker, Y. & Ovaa, H. Tools to investigate the ubiquitin proteasome system. Drug Discov. Today Technol. 26, 25\u201331 (2017).","journal-title":"Drug Discov. Today Technol."},{"key":"5602_CR38","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/978-981-13-1435-3_10","volume":"1088","author":"R Khalil","year":"2018","unstructured":"Khalil, R. Ubiquitin-proteasome pathway and muscle atrophy. Adv. Exp. Med. Biol. 1088, 235\u2013248 (2018).","journal-title":"Adv. Exp. Med. Biol."},{"key":"5602_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1124\/pharmrev.120.000053","volume":"73","author":"SH Barghout","year":"2021","unstructured":"Barghout, S. H. & Schimmer, A. D. E1 enzymes as therapeutic targets in cancer. Pharmacol. Rev. 73, 1\u201358 (2021).","journal-title":"Pharmacol. Rev."},{"key":"5602_CR40","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1146\/annurev-biochem-061516-044859","volume":"86","author":"A Varshavsky","year":"2017","unstructured":"Varshavsky, A. The ubiquitin system, autophagy, and regulated protein degradation. Annu. Rev. Biochem. 86, 123\u2013128 (2017).","journal-title":"Annu. Rev. Biochem."},{"key":"5602_CR41","doi-asserted-by":"publisher","first-page":"24011","DOI":"10.1074\/jbc.M802583200","volume":"283","author":"Z Xia","year":"2008","unstructured":"Xia, Z. et al. Substrate-binding sites of UBR1, the ubiquitin ligase of the N-end rule pathway. J. Biol. Chem. 283, 24011\u201324028 (2008).","journal-title":"J. Biol. Chem."},{"key":"5602_CR42","doi-asserted-by":"publisher","first-page":"e201908087","DOI":"10.1083\/jcb.201908087","volume":"219","author":"D Tang","year":"2020","unstructured":"Tang, D. et al. UBR E3 ligases and the PDIA3 protease control degradation of unfolded antibody heavy chain by ERAD. J. Cell. Biol. 219, e201908087 (2020).","journal-title":"J. Cell. Biol."},{"key":"5602_CR43","doi-asserted-by":"publisher","DOI":"10.1186\/s13062-015-0066-5","volume":"10","author":"G Kaur","year":"2015","unstructured":"Kaur, G. & Subramanian, S. The UBR-box and its relationship to binuclear RING-like treble clef zinc fingers. Biol. Direct 10, 36 (2015).","journal-title":"Biol. Direct"},{"key":"5602_CR44","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1038\/nsmb.1907","volume":"17","author":"WS Choi","year":"2010","unstructured":"Choi, W. S. et al. Structural basis for the recognition of N-end rule substrates by the UBR box of ubiquitin ligases. Nat. Struct. Mol. Biol. 17, 1175\u20131181 (2010).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"5602_CR45","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1038\/s41586-021-04097-8","volume":"600","author":"M Pan","year":"2021","unstructured":"Pan, M. et al. Structural insights into Ubr1-mediated N-degron polyubiquitination. Nature 600, 334\u2013338 (2021).","journal-title":"Nature"},{"key":"5602_CR46","doi-asserted-by":"publisher","DOI":"10.1186\/2193-1801-3-257","volume":"3","author":"K Kitamura","year":"2014","unstructured":"Kitamura, K. The ClpS-like N-domain is essential for the functioning of Ubr11, an N-recognin in Schizosaccharomyces pombe. Springerplus 3, 257 (2014).","journal-title":"Springerplus"},{"key":"5602_CR47","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1016\/j.febslet.2012.11.028","volume":"587","author":"K Kitamura","year":"2013","unstructured":"Kitamura, K. & Fujiwara, H. The type-2 N-end rule peptide recognition activity of Ubr11 ubiquitin ligase is required for the expression of peptide transporters. FEBS Lett. 587, 214\u2013219 (2013).","journal-title":"FEBS Lett."},{"key":"5602_CR48","doi-asserted-by":"publisher","first-page":"1884","DOI":"10.1074\/jbc.M803641200","volume":"284","author":"T Tasaki","year":"2009","unstructured":"Tasaki, T. et al. The substrate recognition domains of the N-end rule pathway. J. Biol. Chem. 284, 1884\u20131895 (2009).","journal-title":"J. Biol. Chem."},{"key":"5602_CR49","doi-asserted-by":"publisher","first-page":"3800","DOI":"10.1073\/pnas.1217358110","volume":"110","author":"T Tasaki","year":"2013","unstructured":"Tasaki, T. et al. UBR box N-recognin-4 (UBR4), an N-recognin of the N-end rule pathway, and its role in yolk sac vascular development and autophagy. Proc. Natl Acad. Sci. USA 110, 3800\u20133805 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5602_CR50","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1007\/s00018-014-1788-8","volume":"72","author":"K Parsons","year":"2015","unstructured":"Parsons, K., Nakatani, Y. & Nguyen, M. D. p600\/UBR4 in the central nervous system. Cell. Mol. Life Sci. 72, 1149\u20131160 (2015).","journal-title":"Cell. Mol. Life Sci."},{"key":"5602_CR51","doi-asserted-by":"publisher","first-page":"e0202260","DOI":"10.1371\/journal.pone.0202260","volume":"13","author":"ST Kim","year":"2018","unstructured":"Kim, S. T. et al. The N-recognin UBR4 of the N-end rule pathway is required for neurogenesis and homeostasis of cell surface proteins. PLoS ONE 13, e0202260 (2018).","journal-title":"PLoS ONE"},{"key":"5602_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21738-8","volume":"12","author":"LC Hunt","year":"2021","unstructured":"Hunt, L. C. et al. Antagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging. Nat. Commun. 12, 1418 (2021).","journal-title":"Nat. Commun."},{"key":"5602_CR53","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/j.celrep.2019.06.094","volume":"28","author":"LC Hunt","year":"2019","unstructured":"Hunt, L. C. et al. A key role for the ubiquitin ligase ubr4 in myofiber hypertrophy in drosophila and mice. Cell Rep. 28, 1268\u20131281 e6 (2019).","journal-title":"Cell Rep."},{"key":"5602_CR54","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1016\/j.str.2017.03.004","volume":"25","author":"J Munoz-Escobar","year":"2017","unstructured":"Munoz-Escobar, J., Matta-Camacho, E., Cho, C., Kozlov, G. & Gehring, K. Bound waters mediate binding of diverse substrates to a ubiquitin ligase. Structure 25, 719\u2013729 e3 (2017).","journal-title":"Structure"},{"key":"5602_CR55","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1016\/j.molcel.2022.02.004","volume":"82","author":"D Sherpa","year":"2022","unstructured":"Sherpa, D., Chrustowicz, J. & Schulman, B. A. How the ends signal the end: regulation by E3 ubiquitin ligases recognizing protein termini. Mol. Cell 82, 1424\u20131438 (2022).","journal-title":"Mol. Cell"},{"key":"5602_CR56","doi-asserted-by":"publisher","first-page":"2092","DOI":"10.1002\/pro.3227","volume":"26","author":"J Munoz-Escobar","year":"2017","unstructured":"Munoz-Escobar, J., Kozlov, G. & Gehring, K. Crystal structure of the UBR-box from UBR6\/FBXO11 reveals domain swapping mediated by zinc binding. Protein Sci. 26, 2092\u20132097 (2017).","journal-title":"Protein Sci."},{"key":"5602_CR57","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbrc.2021.12.041","volume":"590","author":"JA Bhayani","year":"2022","unstructured":"Bhayani, J. A. & Ballicora, M. A. Determination of dissociation constants of protein ligands by thermal shift assay. Biochem. Biophys. Res. Commun. 590, 1\u20136 (2022).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"5602_CR58","doi-asserted-by":"publisher","first-page":"28.9.1","DOI":"10.1002\/0471140864.ps2809s79","volume":"79","author":"K Huynh","year":"2015","unstructured":"Huynh, K. & Partch, C. L. Analysis of protein stability and ligand interactions by thermal shift assay. Curr. Protoc. Protein Sci. 79, 28.9.1\u201328.9.14 (2015).","journal-title":"Curr. Protoc. Protein Sci."},{"key":"5602_CR59","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.1038\/nprot.2014.138","volume":"9","author":"R Jafari","year":"2014","unstructured":"Jafari, R. et al. The cellular thermal shift assay for evaluating drug target interactions in cells. Nat. Protoc. 9, 2100\u20132122 (2014).","journal-title":"Nat. Protoc."},{"key":"5602_CR60","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1038\/nsmb.1894","volume":"17","author":"E Matta-Camacho","year":"2010","unstructured":"Matta-Camacho, E., Kozlov, G., Li, F. F. & Gehring, K. Structural basis of substrate recognition and specificity in the N-end rule pathway. Nat. Struct. Mol. Biol. 17, 1182\u20131187 (2010).","journal-title":"Nat. Struct. Mol. Biol."},{"key":"5602_CR61","doi-asserted-by":"publisher","first-page":"2590","DOI":"10.1074\/jbc.RA119.010912","volume":"295","author":"L Kim","year":"2020","unstructured":"Kim, L., Kwon, D. H., Heo, J., Park, M. R. & Song, H. K. Use of the LC3B-fusion technique for biochemical and structural studies of proteins involved in the N-degron pathway. J. Biol. Chem. 295, 2590\u20132600 (2020).","journal-title":"J. Biol. Chem."},{"key":"5602_CR62","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00085-7","volume":"8","author":"H Cha-Molstad","year":"2017","unstructured":"Cha-Molstad, H. et al. p62\/SQSTM1\/Sequestosome-1 is an N-recognin of the N-end rule pathway which modulates autophagosome biogenesis. Nat. Commun. 8, 102 (2017).","journal-title":"Nat. Commun."},{"key":"5602_CR63","doi-asserted-by":"publisher","first-page":"3725","DOI":"10.1007\/s00018-021-03805-x","volume":"78","author":"T Seo","year":"2021","unstructured":"Seo, T. et al. R-catcher, a potent molecular tool to unveil the arginylome. Cell. Mol. Life Sci. 78, 3725\u20133741 (2021).","journal-title":"Cell. Mol. Life Sci."},{"key":"5602_CR64","doi-asserted-by":"publisher","first-page":"15458","DOI":"10.1074\/jbc.273.25.15458","volume":"273","author":"GB McGaughey","year":"1998","unstructured":"McGaughey, G. B., Gagne, M. & Rappe, A. K. pi-Stacking interactions. Alive and well in proteins. J. Biol. Chem. 273, 15458\u201315463 (1998).","journal-title":"J. Biol. Chem."},{"key":"5602_CR65","doi-asserted-by":"publisher","first-page":"5735","DOI":"10.1021\/ja909084e","volume":"132","author":"TF Headen","year":"2010","unstructured":"Headen, T. F. et al. Structure of pi-pi interactions in aromatic liquids. J. Am. Chem. Soc. 132, 5735\u20135742 (2010).","journal-title":"J. Am. Chem. Soc."},{"key":"5602_CR66","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1021\/ar300265y","volume":"46","author":"DA Dougherty","year":"2013","unstructured":"Dougherty, D. A. The cation-pi interaction. Acc. Chem. Res. 46, 885\u2013893 (2013).","journal-title":"Acc. Chem. Res."},{"key":"5602_CR67","doi-asserted-by":"publisher","first-page":"12596","DOI":"10.1002\/anie.201600547","volume":"55","author":"CR Kennedy","year":"2016","unstructured":"Kennedy, C. R., Lin, S. & Jacobsen, E. N. The cation-pi interaction in small-molecule catalysis. Angew. Chem. Int. Ed. Engl. 55, 12596\u201312624 (2016).","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"5602_CR68","doi-asserted-by":"publisher","first-page":"167035","DOI":"10.1016\/j.jmb.2021.167035","volume":"433","author":"DT Infield","year":"2021","unstructured":"Infield, D. T. et al. Cation-pi interactions and their functional roles in membrane proteins. J. Mol. Biol. 433, 167035 (2021).","journal-title":"J. Mol. Biol."},{"key":"5602_CR69","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1002\/psc.310010507","volume":"1","author":"OD Monera","year":"1995","unstructured":"Monera, O. D., Sereda, T. J., Zhou, N. E., Kay, C. M. & Hodges, R. S. Relationship of sidechain hydrophobicity and alpha-helical propensity on the stability of the single-stranded amphipathic alpha-helix. J. Pept. Sci. 1, 319\u2013329 (1995).","journal-title":"J. Pept. Sci."},{"key":"5602_CR70","doi-asserted-by":"publisher","first-page":"7778","DOI":"10.1021\/jp512766r","volume":"119","author":"MA Trachsel","year":"2015","unstructured":"Trachsel, M. A. et al. Modeling the histidine-phenylalanine interaction: the NH\u2026pi hydrogen bond of imidazole.benzene. J. Phys. Chem. B 119, 7778\u20137790 (2015).","journal-title":"J. Phys. Chem. B"},{"key":"5602_CR71","doi-asserted-by":"publisher","first-page":"19233","DOI":"10.1039\/D2CP02048C","volume":"24","author":"RM Steinert","year":"2022","unstructured":"Steinert, R. M., Kasireddy, C., Heikes, M. E. & Mitchell-Koch, K. R. Newly identified C-Hcdots, three dots, centeredO hydrogen bond in histidine. Phys. Chem. Chem. Phys. 24, 19233\u201319251 (2022).","journal-title":"Phys. Chem. Chem. Phys."},{"key":"5602_CR72","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1038\/s41592-020-0848-2","volume":"17","author":"JK Leman","year":"2020","unstructured":"Leman, J. K. et al. Macromolecular modeling and design in Rosetta: recent methods and frameworks. Nat. Methods 17, 665\u2013680 (2020).","journal-title":"Nat. Methods"},{"key":"5602_CR73","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1146\/annurev.biochem.77.062906.171838","volume":"77","author":"R Das","year":"2008","unstructured":"Das, R. & Baker, D. Macromolecular modeling with rosetta. Annu. Rev. Biochem. 77, 363\u2013382 (2008).","journal-title":"Annu. Rev. Biochem."},{"key":"5602_CR74","doi-asserted-by":"publisher","first-page":"2987","DOI":"10.1021\/bi902153g","volume":"49","author":"KW Kaufmann","year":"2010","unstructured":"Kaufmann, K. W., Lemmon, G. H., Deluca, S. L., Sheehan, J. H. & Meiler, J. Practically useful: what the Rosetta protein modeling suite can do for you. Biochemistry 49, 2987\u20132998 (2010).","journal-title":"Biochemistry"},{"key":"5602_CR75","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1002\/prot.26194","volume":"89","author":"I Anishchenko","year":"2021","unstructured":"Anishchenko, I. et al. Protein tertiary structure prediction and refinement using deep learning and Rosetta in CASP14. Proteins 89, 1722\u20131733 (2021).","journal-title":"Proteins"},{"key":"5602_CR76","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1002\/prot.22921","volume":"79","author":"EH Kellogg","year":"2011","unstructured":"Kellogg, E. H., Leaver-Fay, A. & Baker, D. Role of conformational sampling in computing mutation-induced changes in protein structure and stability. Proteins 79, 830\u2013838 (2011).","journal-title":"Proteins"},{"key":"5602_CR77","doi-asserted-by":"publisher","first-page":"6201","DOI":"10.1021\/acs.jctc.6b00819","volume":"12","author":"H Park","year":"2016","unstructured":"Park, H. et al. Simultaneous optimization of biomolecular energy functions on features from small molecules and macromolecules. J. Chem. Theory Comput. 12, 6201\u20136212 (2016).","journal-title":"J. Chem. Theory Comput."},{"key":"5602_CR78","doi-asserted-by":"publisher","first-page":"3031","DOI":"10.1021\/acs.jctc.7b00125","volume":"13","author":"RF Alford","year":"2017","unstructured":"Alford, R. F. et al. The Rosetta all-atom energy function for macromolecular modeling and design. J. Chem. Theory Comput. 13, 3031\u20133048 (2017).","journal-title":"J. Chem. Theory Comput."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05602-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05602-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05602-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T13:10:53Z","timestamp":1701263453000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05602-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,29]]},"references-count":78,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["5602"],"URL":"https:\/\/doi.org\/10.1038\/s42003-023-05602-7","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,29]]},"assertion":[{"value":"21 May 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1214"}}