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  • Chen, GefeiUppsala universitet,Strukturbiologi,Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden (author)

Molecular basis for different substrate-binding sites and chaperone functions of the BRICHOS domain

  • Article/chapterEnglish2024

Publisher, publication year, extent ...

  • Wiley,2024
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:kth-348308
  • https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-348308URI
  • https://doi.org/10.1002/pro.5063DOI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-534280URI

Supplementary language notes

  • Language:English
  • Summary in:English

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Classification

  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • QC 20240704
  • Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone domain, found in several otherwise unrelated proproteins that contain amyloidogenic regions, effectively inhibits amyloid formation and toxicity but can in some cases also prevent non-fibrillar, amorphous protein aggregation. Here, we elucidate the molecular basis behind the multifaceted chaperone activities of the BRICHOS domain from the Bri2 proprotein. High-confidence AlphaFold2 and RoseTTAFold predictions suggest that the intramolecular amyloidogenic region (Bri23) is part of the hydrophobic core of the proprotein, where it occupies the proposed amyloid binding site, explaining the markedly reduced ability of the proprotein to prevent an exogenous amyloidogenic peptide from aggregating. However, the BRICHOS-Bri23 complex maintains its ability to form large polydisperse oligomers that prevent amorphous protein aggregation. A cryo-EM-derived model of the Bri2 BRICHOS oligomer is compatible with surface-exposed hydrophobic motifs that get exposed and come together during oligomerization, explaining its effects against amorphous aggregation. These findings provide a molecular basis for the BRICHOS chaperone domain function, where distinct surfaces are employed against different forms of protein aggregation.

Subject headings and genre

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  • Wang, YuDepartment of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China,Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Northeast Forestry Univ, Coll Wildlife & Protected Area, Harbin, Peoples R China. (author)
  • Zheng, ZihanDepartment of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden; Department of Pharmacology, Xi'an Jiaotong University, Xi'an, China,Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Xi An Jiao Tong Univ, Dept Pharmacol, Xian, Peoples R China. (author)
  • Jiang, WangshuUppsala universitet,Strukturbiologi(Swepub:uu)wanji332 (author)
  • Leppert, AxelDepartment of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden,Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden. (author)
  • Zhong, XueyingKTH,Strukturell bioteknik,KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Sch Engn Sci Chem Biotechnol & Hlth, Huddinge, Sweden.(Swepub:kth)u169038p (author)
  • Belorusova, AnnaZoBio BV, Leiden, The Netherlands (author)
  • Siegal, GreggZoBio BV, Leiden, The Netherlands (author)
  • Jegerschöld, CarolineKTH,Ergonomi,KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Sch Engn Sci Chem Biotechnol & Hlth, Huddinge, Sweden.(Swepub:kth)u14svzvm (author)
  • Koeck, Philip J. B.KTH,Strukturell bioteknik,KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Sch Engn Sci Chem Biotechnol & Hlth, Huddinge, Sweden.,Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.(Swepub:kth)u1ikssgh (author)
  • Abelein, AxelDepartment of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden,Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden.;Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Solna, Sweden. (author)
  • Hebert, HansKTH,Strukturell bioteknik,KTH Royal Inst Technol, Dept Biomed Engn & Hlth Syst, Sch Engn Sci Chem Biotechnol & Hlth, Huddinge, Sweden.(Swepub:kth)u1h8ygcn (author)
  • Knight, Stefan D.Uppsala universitet,Strukturbiologi(Swepub:uu)stkni677 (author)
  • Johansson, JanDepartment of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden (author)
  • Uppsala universitetStrukturbiologi (creator_code:org_t)

Related titles

  • In:Protein Science: Wiley33:70961-83681469-896X

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