{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T21:14:14Z","timestamp":1762377254485,"version":"3.41.2"},"reference-count":65,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T00:00:00Z","timestamp":1668556800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Protein Science"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Signal peptide (SP) plays an important role in membrane targeting for insertion of secretory and membrane proteins during translocation processes in prokaryotes and eukaryotes. Beside the targeting functions, SP has also been found to affect the stability and folding of several proteins. Serum amyloid A (SAA) proteins are apolipoproteins responding to acute\u2010phase inflammation. The fibrillization of SAA results in a protein misfolding disease named amyloid A (AA) amyloidosis. The main disease\u2010associated isoform of human SAA, SAA1.1, is expressed as a precursor protein with an N\u2010terminal signal peptide composed of 18 residues. The cleavage of the SP generates mature SAA1.1. To investigate whether the SP affects properties of SAA1.1, we systematically examined the structure, protein stability, and fibrillization propensity of pre\u2010SAA1.1, which possesses the SP, and Ser\u2010SAA1.1 without the SP but containing with an additional N\u2010terminal serine residue. We found that the presence of the SP did not significantly affect the predominant helical structure but changed the tertiary conformation as evidenced by intrinsic fluorescence and exposed hydrophobic surfaces. Pre\u2010SAA1.1 and Ser\u2010SAA1.1 formed distinct oligomeric assemblies in which pre\u2010SAA1.1 populated as tetramer and octamer, whereas Ser\u2010SAA1.1 existed as a predominant hexamer. Pre\u2010SAA1.1 was found significantly more stable than Ser\u2010SAA1.1 upon thermal and chemical unfolding. Ser\u2010SAA1.1, but not pre\u2010SAA1.1, is capable of forming amyloid fibrils in protein misfolding study, indicating a protective role of the SP. Altogether, our results demonstrated a novel role of the SP in SAA folding and misfolding and provided a novel direction for therapeutic development of AA amyloidosis.<\/jats:p>","DOI":"10.1002\/pro.4485","type":"journal-article","created":{"date-parts":[[2022,10,30]],"date-time":"2022-10-30T18:04:31Z","timestamp":1667153071000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Signal peptide stabilizes folding and inhibits misfolding of serum amyloid A"],"prefix":"10.1002","volume":"31","author":[{"given":"Jin\u2010Lin","family":"Wu","sequence":"first","affiliation":[{"name":"Ph.D. Program for Cancer Biology and Drug Discovery China Medical University and Academia Sinica  Taichung Taiwan"},{"name":"Genomics Research Center, Academia Sinica  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6596-6338","authenticated-orcid":false,"given":"Yun\u2010Ru","family":"Chen","sequence":"additional","affiliation":[{"name":"Ph.D. Program for Cancer Biology and Drug Discovery China Medical University and Academia Sinica  Taichung Taiwan"},{"name":"Genomics Research Center, Academia Sinica  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,11,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ge.24.120190.001243"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cb.10.110194.000511"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(85)90046-4"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(86)90394-3"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01868635"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a012872"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.048"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr010166y"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.23.9213"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3278378"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi0360509"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/la900198h"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063442"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M505834200"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi011037e"},{"key":"e_1_2_10_17_1","first-page":"1361","article-title":"Serum amyloid a as a tumor marker in sera of nude mice with orthotopic human pancreatic cancer and in plasma of patients with pancreatic cancer","volume":"27","author":"Yokoi K","year":"2005","journal-title":"Int J Oncol"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-006-9091-z"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6605720"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.27942"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-016-2882-0"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-09713-9"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)67562-3"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867323666160418114600"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acc.2019.01.002"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0925-4439(94)00076-3"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00428-001-0582-9"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-41769-7_17"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi00333a018"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1322357111"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2011.03.090"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.23188"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/bip.360310111"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602363200"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.177246"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.222681699"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.038133"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-551-0_3"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.10.084"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.13443"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(89)90046-8"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2010.04.001"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.2147\/CLEP.S39981"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-19294-9_8"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1080\/13506129.2020.1835263"},{"key":"e_1_2_10_46_1","first-page":"770","article-title":"Systemic amyloidosis: Novel therapies and role of biomarkers","volume":"32","author":"Nuvolone M","year":"2017","journal-title":"Nephrol Dial Transplant"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-94-007-5416-4_20"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9149(97)89403-9"},{"key":"e_1_2_10_49_1","first-page":"178","article-title":"Amyloid heart disease. New frontiers and insights in pathophysiology, diagnosis, and management","volume":"32","author":"Hassan W","year":"2005","journal-title":"Tex Heart Inst J"},{"key":"e_1_2_10_50_1","first-page":"343","article-title":"Clinical outcome and survival of secondary (aa) amyloidosis","volume":"21","author":"Tanaka F","year":"2003","journal-title":"Clin Exp Rheumatol"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1110\/ps.04627004"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi980274n"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020712-163913"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3181041"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja909345p"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.03206"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1910713116"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.9.12.2117"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-006-1792-3"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa065644"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-015-2167-y"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2020.108264"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121005109"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.045187"},{"key":"e_1_2_10_65_1","first-page":"11","article-title":"Determination of peptide oligomerization state using rapid photochemical crosslinking","volume":"299","author":"Vollers SS","year":"2005","journal-title":"Methods Mol Biol"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(84)90309-7"}],"container-title":["Protein Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.4485","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pro.4485","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pro.4485","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T08:21:14Z","timestamp":1692519674000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pro.4485"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,16]]},"references-count":65,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["10.1002\/pro.4485"],"URL":"https:\/\/doi.org\/10.1002\/pro.4485","archive":["Portico"],"relation":{},"ISSN":["0961-8368","1469-896X"],"issn-type":[{"type":"print","value":"0961-8368"},{"type":"electronic","value":"1469-896X"}],"subject":[],"published":{"date-parts":[[2022,11,16]]},"assertion":[{"value":"2022-09-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-10-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e4485"}}