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Both PGRN and GRNs are implicated in a plethora of biological functions, often in opposing roles to each other. Lately, GRNs have generated significant attention due to their implicated roles in neurodegenerative disorders. Despite their physiological and pathological significance, the structure\u2010function relationships of GRNs are poorly defined. GRNs contain 12 conserved cysteines forming six intramolecular disulfide bonds, making them rather exceptional, even among a few proteins with high disulfide bond density. Solution NMR investigations in the past have revealed a unique structure containing putative interdigitated disulfide bonds for several GRNs, but GRN\u20103 was unsolvable due to its heterogeneity and disorder. In our previous report, we showed that abrogation of disulfide bonds in GRN\u20103 renders the protein completely disordered (Ghag et al., Prot Eng Des Sel 2016). In this study, we report the cellular expression and biophysical analysis of fully oxidized, native GRN\u20103. Our results indicate that both <jats:italic>E. coli<\/jats:italic> and human embryonic kidney (HEK) cells do not exclusively make GRN\u20103 with homogenous disulfide bonds, likely due to the high cysteine density within the protein. Biophysical analysis suggests that GRN\u20103 structure is dominated by irregular loops held together only by disulfide bonds, which induced remarkable thermal stability to the protein despite the lack of regular secondary structure. This unusual handshake between disulfide bonds and disorder within GRN\u20103 could suggest a unique adaptation of intrinsically disordered proteins towards structural stability.<\/jats:p>","DOI":"10.1002\/pro.3212","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T01:12:44Z","timestamp":1497316364000},"page":"1759-1772","source":"Crossref","is-referenced-by-count":27,"title":["Disulfide bonds and disorder in granulin\u20103: An unusual handshake between structural stability and plasticity"],"prefix":"10.1002","volume":"26","author":[{"given":"Gaurav","family":"Ghag","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Southern Mississippi Hattiesburg Mississippi 39406"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Holler","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Emory University School of Medicine Atlanta Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Taylor","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Emory University School of Medicine Atlanta Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas L.","family":"Kukar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Emory University School of Medicine Atlanta Georgia 30322"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir N.","family":"Uversky","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine University of South Florida Tampa Florida 33612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayaraghavan","family":"Rangachari","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Southern Mississippi Hattiesburg Mississippi 39406"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,6,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(05)80908-8"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.1580145"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.5.1715"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-009-0616-y"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2008.10.021"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2012.11.032"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1533317508321910"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2580"},{"key":"e_1_2_6_10_1","first-page":"5331","article-title":"Biological activities and signaling pathways of the granulin\/epithelin precursor","volume":"59","author":"Zanocco\u2010Marani T","year":"1999","journal-title":"Cancer Res"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-011-9569-4"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05016"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.64.10.1436"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05017"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)01141-8"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)42382-4"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002290200"},{"key":"e_1_2_6_18_1","first-page":"169","article-title":"Structure of human plasminogen kringle 4 at 1.68 \u00c5 and 277 K. 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