{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:22:46Z","timestamp":1790360566043,"version":"4.1.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T00:00:00Z","timestamp":1456272000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T00:00:00Z","timestamp":1456272000000},"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":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher protein concentrations are often problematic. This raises the question whether the solubility of natural protein sequences can be improved. We here show an anti-correlation between the number of aggregation prone regions (APRs) in a protein sequence and its solubility, suggesting that mutational suppression of APRs provides a simple strategy to increase protein solubility. We show that mutations at specific positions within a protein structure can act as APR suppressors without affecting protein stability. These hot spots for protein solubility are both structure and sequence dependent but can be computationally predicted. We demonstrate this by reducing the aggregation of human \u03b1-galactosidase and protective antigen of\n                    <jats:italic>Bacillus anthracis<\/jats:italic>\n                    through mutation. Our results indicate that many proteins possess hot spots allowing to adapt protein solubility independently of structure and function.\n                  <\/jats:p>","DOI":"10.1038\/ncomms10816","type":"journal-article","created":{"date-parts":[[2016,2,24]],"date-time":"2016-02-24T06:02:01Z","timestamp":1456293721000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Structural hot spots for the solubility of globular proteins"],"prefix":"10.1038","volume":"7","author":[{"given":"Ashok","family":"Ganesan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Siekierska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacinte","family":"Beerten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke","family":"Brams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Van Durme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greet","family":"De Baets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rob","family":"Van der Kant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Gallardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meine","family":"Ramakers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Langenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Wilkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"De Smet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Ulens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Rousseau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Schymkowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,2,24]]},"reference":[{"key":"BFncomms10816_CR1","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1074\/mcp.M113.033076","volume":"13","author":"AM Mehdi","year":"2014","unstructured":"Mehdi, A. M., Patrick, R., Bailey, T. L. & Boden, M. Predicting the dynamics of protein abundance. Mol. Cell. Proteomics 13, 1330\u20131340 (2014).","journal-title":"Mol. Cell. Proteomics"},{"key":"BFncomms10816_CR2","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/S0968-0004(01)01938-7","volume":"26","author":"RJ Ellis","year":"2001","unstructured":"Ellis, R. J. Macromolecular crowding: obvious but underappreciated. Trends Biochem. Sci. 26, 597\u2013604 (2001).","journal-title":"Trends Biochem. Sci."},{"key":"BFncomms10816_CR3","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1039\/b913099n","volume":"5","author":"GG Tartaglia","year":"2009","unstructured":"Tartaglia, G. G. & Vendruscolo, M. Correlation between mRNA expression levels and protein aggregation propensities in subcellular localisations. Mol. Biosyst. 5, 1873\u20131876 (2009).","journal-title":"Mol. Biosyst."},{"key":"BFncomms10816_CR4","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.jmb.2009.03.002","volume":"388","author":"GG Tartaglia","year":"2009","unstructured":"Tartaglia, G. G., Pechmann, S., Dobson, C. M. & Vendruscolo, M. A relationship between mRNA expression levels and protein solubility in E. coli. J. Mol. Biol. 388, 381\u2013389 (2009).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR5","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1002\/biot.201100014","volume":"6","author":"V Castillo","year":"2011","unstructured":"Castillo, V., Grana-Montes, R. & Ventura, S. The aggregation properties of Escherichia coli proteins associated with their cellular abundance. Biotechnol. J. 6, 752\u2013760 (2011).","journal-title":"Biotechnol. J."},{"key":"BFncomms10816_CR6","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.tibs.2007.03.005","volume":"32","author":"GG Tartaglia","year":"2007","unstructured":"Tartaglia, G. G., Pechmann, S., Dobson, C. M. & Vendruscolo, M. Life on the edge: a link between gene expression levels and aggregation rates of human proteins. Trends Biochem. Sci. 32, 204\u2013206 (2007).","journal-title":"Trends Biochem. Sci."},{"key":"BFncomms10816_CR7","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/j.jmb.2010.08.013","volume":"402","author":"GG Tartaglia","year":"2010","unstructured":"Tartaglia, G. G. & Vendruscolo, M. Proteome-level interplay between folding and aggregation propensities of proteins. J. Mol. Biol. 402, 919\u2013928 (2010).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR8","doi-asserted-by":"publisher","first-page":"e1002090","DOI":"10.1371\/journal.pcbi.1002090","volume":"7","author":"G De Baets","year":"2011","unstructured":"De Baets, G. et al. An evolutionary trade-off between protein turnover rate and protein aggregation favors a higher aggregation propensity in fast degrading proteins. PLoS Comput. Biol. 7, e1002090 (2011).","journal-title":"PLoS Comput. Biol."},{"key":"BFncomms10816_CR9","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.jmb.2004.06.088","volume":"342","author":"R Linding","year":"2004","unstructured":"Linding, R., Schymkowitz, J., Rousseau, F., Diella, F. & Serrano, L. A comparative study of the relationship between protein structure and beta-aggregation in globular and intrinsically disordered proteins. J. Mol. Biol. 342, 345\u2013353 (2004).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR10","doi-asserted-by":"publisher","first-page":"16672","DOI":"10.1073\/pnas.0505905102","volume":"102","author":"A Esteras-Chopo","year":"2005","unstructured":"Esteras-Chopo, A., Serrano, L. & de la Paz, M. L. The amyloid stretch hypothesis: recruiting proteins toward the dark side. Proc. Natl Acad. Sci. USA 102, 16672\u201316677 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms10816_CR11","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1093\/protein\/gzp037","volume":"22","author":"PK Teng","year":"2009","unstructured":"Teng, P. K. & Eisenberg, D. Short protein segments can drive a non-fibrillizing protein into the amyloid state. Protein Eng. Des. Sel. 22, 531\u2013536 (2009).","journal-title":"Protein Eng. Des. Sel."},{"key":"BFncomms10816_CR12","doi-asserted-by":"publisher","first-page":"7258","DOI":"10.1073\/pnas.0308249101","volume":"101","author":"S Ventura","year":"2004","unstructured":"Ventura, S. et al. Short amino acid stretches can mediate amyloid formation in globular proteins: the Src homology 3 (SH3) case. Proc. Natl Acad. Sci. USA 101, 7258\u20137263 (2004).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms10816_CR13","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1038\/nbt1012","volume":"22","author":"AM Fernandez-Escamilla","year":"2004","unstructured":"Fernandez-Escamilla, A. M., Rousseau, F., Schymkowitz, J. & Serrano, L. Prediction of sequence-dependent and mutational effects on the aggregation of peptides and proteins. Nat. Biotechnol. 22, 1302\u20131306 (2004).","journal-title":"Nat. Biotechnol."},{"key":"BFncomms10816_CR14","doi-asserted-by":"publisher","first-page":"3487","DOI":"10.1073\/pnas.0915166107","volume":"107","author":"L Goldschmidt","year":"2010","unstructured":"Goldschmidt, L., Teng, P. K., Riek, R. & Eisenberg, D. Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proc. Natl Acad. Sci. USA 107, 3487\u20133492 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms10816_CR15","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.jmb.2011.12.005","volume":"421","author":"F Agostini","year":"2012","unstructured":"Agostini, F., Vendruscolo, M. & Tartaglia, G. G. Sequence-based prediction of protein solubility. J. Mol. Biol. 421, 237\u2013241 (2012).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR16","first-page":"525","volume":"12","author":"RW Hooft","year":"1996","unstructured":"Hooft, R. W., Sander, C., Scharf, M. & Vriend, G. The PDBFINDER database: a summary of PDB, DSSP and HSSP information with added value. Comput. Appl. Biosci. 12, 525\u2013529 (1996).","journal-title":"Comput. Appl. Biosci."},{"key":"BFncomms10816_CR17","doi-asserted-by":"publisher","first-page":"4201","DOI":"10.1073\/pnas.0811922106","volume":"106","author":"T Niwa","year":"2009","unstructured":"Niwa, T. et al. Bimodal protein solubility distribution revealed by an aggregation analysis of the entire ensemble of Escherichia coli proteins. Proc. Natl Acad. Sci. USA 106, 4201\u20134206 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms10816_CR18","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/nrg3185","volume":"13","author":"C Vogel","year":"2012","unstructured":"Vogel, C. & Marcotte, E. M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13, 227\u2013232 (2012).","journal-title":"Nat. Rev. Genet."},{"key":"BFncomms10816_CR19","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/j.jmb.2005.11.035","volume":"355","author":"F Rousseau","year":"2006","unstructured":"Rousseau, F., Serrano, L. & Schymkowitz, J. W. How evolutionary pressure against protein aggregation shaped chaperone specificity. J. Mol. Biol. 355, 1037\u20131047 (2006).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR20","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/j.jmb.2005.11.035","volume":"355","author":"F Rousseau","year":"2006","unstructured":"Rousseau, F. & Serrano, L. Schymkowitz JWH. How evolutionary pressure against protein aggregation shaped chaperone specificity. J. Mol. Biol. 355, 1037\u20131047 (2006).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR21","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1016\/j.jmb.2014.04.007","volume":"426","author":"G De Baets","year":"2014","unstructured":"De Baets, G., Van Durme, J., Rousseau, F. & Schymkowitz, J. A genome-wide sequence-structure analysis suggests aggregation gatekeepers constitute an evolutionary constrained functional class. J. Mol. Biol. 426, 2405\u20132412 (2014).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR22","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1107\/S0021889896008631","volume":"29","author":"RWW Hooft","year":"1996","unstructured":"Hooft, R. W. W., Sander, C. & Vriend, G. Verification of protein structures: side-chain planarity. J. Appl. Crystallogr. 29, 714\u2013716 (1996).","journal-title":"J. Appl. Crystallogr."},{"key":"BFncomms10816_CR23","doi-asserted-by":"publisher","first-page":"W382","DOI":"10.1093\/nar\/gki387","volume":"33","author":"J Schymkowitz","year":"2005","unstructured":"Schymkowitz, J. et al. The FoldX web server: an online force field. Nucleic Acids Res. 33, W382\u2013W388 (2005).","journal-title":"Nucleic Acids Res."},{"key":"BFncomms10816_CR24","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1074\/mcp.O111.014704","volume":"11","author":"M Wang","year":"2012","unstructured":"Wang, M. et al. PaxDb, a database of protein abundance averages across all three domains of life. Mol. Cell. Proteomics 11, 492\u2013500 (2012).","journal-title":"Mol. Cell. Proteomics"},{"key":"BFncomms10816_CR25","doi-asserted-by":"publisher","first-page":"1163","DOI":"10.1056\/NEJM196705252762101","volume":"276","author":"RO Brady","year":"1967","unstructured":"Brady, R. O. et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N. Engl. J. Med. 276, 1163\u20131167 (1967).","journal-title":"N. Engl. J. Med."},{"key":"BFncomms10816_CR26","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1002\/humu.1380030204","volume":"3","author":"CM Eng","year":"1994","unstructured":"Eng, C. M. & Desnick, R. J. Molecular basis of Fabry disease: mutations and polymorphisms in the human alpha-galactosidase A gene. Hum. Mutat. 3, 103\u2013111 (1994).","journal-title":"Hum. Mutat."},{"key":"BFncomms10816_CR27","doi-asserted-by":"publisher","first-page":"28386","DOI":"10.1074\/jbc.M112.351056","volume":"287","author":"A Siekierska","year":"2012","unstructured":"Siekierska, A. et al. Alpha-galactosidase aggregation is a determinant of pharmacological chaperone efficacy on Fabry disease mutants. J. Biol. Chem. 287, 28386\u201328397 (2012).","journal-title":"J. Biol. Chem."},{"key":"BFncomms10816_CR28","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.mam.2009.06.003","volume":"30","author":"RJ Collier","year":"2009","unstructured":"Collier, R. J. Membrane translocation by anthrax toxin. Mol. Aspects Med. 30, 413\u2013422 (2009).","journal-title":"Mol. Aspects Med."},{"key":"BFncomms10816_CR29","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1016\/j.addr.2005.01.028","volume":"57","author":"RN Brey","year":"2005","unstructured":"Brey, R. N. Molecular basis for improved anthrax vaccines. Adv. Drug. Deliv. Rev. 57, 1266\u20131292 (2005).","journal-title":"Adv. Drug. Deliv. Rev."},{"key":"BFncomms10816_CR30","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/j.bbrc.2004.08.020","volume":"322","author":"S Singh","year":"2004","unstructured":"Singh, S. et al. Thermal inactivation of protective antigen of Bacillus anthracis and its prevention by polyol osmolytes. Biochem. Biophys. Res. Commun. 322, 1029\u20131037 (2004).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFncomms10816_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.abb.2007.04.030","volume":"465","author":"DA Chalton","year":"2007","unstructured":"Chalton, D. A. et al. Unfolding transitions of Bacillus anthracis protective antigen. Arch. Biochem. Biophys. 465, 1\u201310 (2007).","journal-title":"Arch. Biochem. Biophys."},{"key":"BFncomms10816_CR32","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/385833a0","volume":"385","author":"C Petosa","year":"1997","unstructured":"Petosa, C., Collier, R. J., Klimpel, K. R., Leppla, S. H. & Liddington, R. C. Crystal structure of the anthrax toxin protective antigen. Nature 385, 833\u2013838 (1997).","journal-title":"Nature"},{"key":"BFncomms10816_CR33","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1016\/j.ejpb.2012.05.019","volume":"82","author":"A Ganesan","year":"2012","unstructured":"Ganesan, A., Watkinson, A. & Moore, B. D. Biophysical characterisation of thermal-induced precipitates of recombinant anthrax protective antigen: evidence for kinetically trapped unfolding domains in solid-state. Eur. J. Pharm. Biopharm. 82, 475\u2013484 (2012).","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"BFncomms10816_CR34","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1002\/biot.200800091","volume":"3","author":"P Garidel","year":"2008","unstructured":"Garidel, P., Hegyi, M., Bassarab, S. & Weichel, M. A rapid, sensitive and economical assessment of monoclonal antibody conformational stability by intrinsic tryptophan fluorescence spectroscopy. Biotechnol. J. 3, 1201\u20131211 (2008).","journal-title":"Biotechnol. J."},{"key":"BFncomms10816_CR35","doi-asserted-by":"publisher","first-page":"84","DOI":"10.3109\/10837450.2014.910808","volume":"20","author":"AR Karow","year":"2015","unstructured":"Karow, A. R., Gotzl, J. & Garidel, P. Resolving power of dynamic light scattering for protein and polystyrene nanoparticles. Pharm. Dev. Technol. 20, 84\u201389 (2015).","journal-title":"Pharm. Dev. Technol."},{"key":"BFncomms10816_CR36","doi-asserted-by":"publisher","first-page":"4209","DOI":"10.1002\/pmic.201000327","volume":"10","author":"JM Laurent","year":"2010","unstructured":"Laurent, J. M. et al. Protein abundances are more conserved than mRNA abundances across diverse taxa. Proteomics 10, 4209\u20134212 (2010).","journal-title":"Proteomics"},{"key":"BFncomms10816_CR37","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1021\/bi100978r","volume":"50","author":"E Sahin","year":"2011","unstructured":"Sahin, E. et al. Computational design and biophysical characterization of aggregation-resistant point mutations for gamma D crystallin illustrate a balance of conformational stability and intrinsic aggregation propensity. Biochemistry 50, 628\u2013639 (2011).","journal-title":"Biochemistry"},{"key":"BFncomms10816_CR38","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1007\/s11095-011-0538-y","volume":"29","author":"A Zhang","year":"2012","unstructured":"Zhang, A., Singh, S. K., Shirts, M. R., Kumar, S. & Fernandez, E. J. distinct aggregation mechanisms of monoclonal antibody under thermal and freeze-thaw stresses revealed by hydrogen exchange. Pharm. Res. 29, 236\u2013250 (2012).","journal-title":"Pharm. Res."},{"key":"BFncomms10816_CR39","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/978-1-61779-921-1_26","volume":"899","author":"PM Buck","year":"2012","unstructured":"Buck, P. M. et al. Computational methods to predict therapeutic protein aggregation. Methods. Mol. Biol. 899, 425\u2013451 (2012).","journal-title":"Methods. Mol. Biol."},{"key":"BFncomms10816_CR40","doi-asserted-by":"publisher","first-page":"2637","DOI":"10.1002\/prot.23085","volume":"79","author":"JM Perchiacca","year":"2011","unstructured":"Perchiacca, J. M., Bhattacharya, M. & Tessier, P. M. Mutational analysis of domain antibodies reveals aggregation hotspots within and near the complementarity determining regions. Proteins 79, 2637\u20132647 (2011).","journal-title":"Proteins"},{"key":"BFncomms10816_CR41","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1038\/nbt1000","volume":"22","author":"L Jespers","year":"2004","unstructured":"Jespers, L., Schon, O., Famm, K. & Winter, G. Aggregation-resistant domain antibodies selected on phage by heat denaturation. Nat. Biotechnol. 22, 1161\u20131165 (2004).","journal-title":"Nat. Biotechnol."},{"key":"BFncomms10816_CR42","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1093\/protein\/gzt058","volume":"27","author":"JM Perchiacca","year":"2014","unstructured":"Perchiacca, J. M., Lee, C. C. & Tessier, P. M. Optimal charged mutations in the complementarity-determining regions that prevent domain antibody aggregation are dependent on the antibody scaffold. Protein Eng. Des. Sel. 27, 29\u201339 (2014).","journal-title":"Protein Eng. Des. Sel."},{"key":"BFncomms10816_CR43","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.febslet.2013.11.029","volume":"588","author":"R Rouet","year":"2014","unstructured":"Rouet, R., Lowe, D. & Christ, D. Stability engineering of the human antibody repertoire. FEBS Lett. 588, 269\u2013277 (2014).","journal-title":"FEBS Lett."},{"key":"BFncomms10816_CR44","doi-asserted-by":"publisher","first-page":"2405","DOI":"10.1016\/j.jmb.2014.04.007","volume":"526","author":"G De Baets","year":"2014","unstructured":"De Baets, G., Van Durme, J., Rousseau, F. & Schymkowitz, J. A genome-wide sequence-structure analysis suggests aggregation gatekeepers constitute an evolutionary constrained functional class. J. Mol. Biol. 526, 2405\u20132412 (2014).","journal-title":"J. Mol. Biol."},{"key":"BFncomms10816_CR45","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/sj.embor.7401034","volume":"8","author":"E Monsellier","year":"2007","unstructured":"Monsellier, E. & Chiti, F. Prevention of amyloid-like aggregation as a driving force of protein evolution. EMBO. Rep. 8, 737\u2013742 (2007).","journal-title":"EMBO. Rep."},{"key":"BFncomms10816_CR46","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0009-8981(81)90384-3","volume":"112","author":"JS Mayes","year":"1981","unstructured":"Mayes, J. S., Scheerer, J. B., Sifers, R. N. & Donaldson, M. L. Differential assay for lysosomal alpha-galactosidases in human tissues and its application to Fabry\u2019s disease. Clin. Chim. Acta 112, 247\u2013251 (1981).","journal-title":"Clin. Chim. Acta"},{"key":"BFncomms10816_CR47","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1107\/S0907444909047337","volume":"66","author":"W Kabsch","year":"2010","unstructured":"Kabsch, W. XDS. Acta Crystallogr. D. Biol. Crystallogr. 66, 125\u2013132 (2010).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"BFncomms10816_CR48","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1107\/S0907444910045749","volume":"67","author":"MD Winn","year":"2011","unstructured":"Winn, M. D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr. D. Biol. Crystallogr. 67, 235\u2013242 (2011).","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"BFncomms10816_CR49","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S0907444909052925","volume":"66","author":"PD Adams","year":"2010","unstructured":"Adams, P. D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta. Crystallogr. D. Biol. Crystallogr. 66, 213\u2013221 (2010).","journal-title":"Acta. Crystallogr. D. Biol. Crystallogr."},{"key":"BFncomms10816_CR50","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","volume":"66","author":"P Emsley","year":"2010","unstructured":"Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta. Crystallogr. D. Biol. Crystallogr. 66, 486\u2013501 (2010).","journal-title":"Acta. Crystallogr. D. Biol. Crystallogr."},{"key":"BFncomms10816_CR51","doi-asserted-by":"publisher","first-page":"18378","DOI":"10.1073\/pnas.1208280109","volume":"109","author":"AF Kintzer","year":"2012","unstructured":"Kintzer, A. F., Tang, I. I., Schawel, A. K., Brown, M. J. & Krantz, B. A. Anthrax toxin protective antigen integrates poly-gamma-D-glutamate and pH signals to sense the optimal environment for channel formation. Proc. Natl Acad. Sci. USA 109, 18378\u201318383 (2012).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms10816_CR52","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1107\/S0907444909042073","volume":"66","author":"VB Chen","year":"2010","unstructured":"Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta. Crystallogr. D. Biol. Crystallogr. 66, 12\u201321 (2010).","journal-title":"Acta. Crystallogr. D. Biol. Crystallogr."},{"key":"BFncomms10816_CR53","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1002\/prot.10104","volume":"47","author":"E Krieger","year":"2002","unstructured":"Krieger, E., Koraimann, G. & Vriend, G. Increasing the precision of comparative models with YASARA NOVA--a self-parameterizing force field. Proteins 47, 393\u2013402 (2002).","journal-title":"Proteins"},{"key":"BFncomms10816_CR54","doi-asserted-by":"publisher","first-page":"4816","DOI":"10.1021\/bi9002265","volume":"48","author":"RL Lieberman","year":"2009","unstructured":"Lieberman, R. L., D'Aquino, J. A., Ringe, D. & Petsko, G. A. Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability. Biochemistry 48, 4816\u20134827 (2009).","journal-title":"Biochemistry"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms10816.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms10816","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms10816.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T06:46:05Z","timestamp":1672814765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms10816"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,24]]},"references-count":54,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,4,22]]}},"alternative-id":["BFncomms10816"],"URL":"https:\/\/doi.org\/10.1038\/ncomms10816","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,2,24]]},"assertion":[{"value":"28 January 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.S., A.G., F.D.S., J.V.D., F.R. and J.S. are mentioned as inventors on a patent filed by the host institute VIB entitled \u2018Means and methods for generating improved proteins\u2019. The authors declare no other financial interests in this work.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10816"}}