Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core.
| العنوان: | Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core. |
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| المؤلفون: | Richards LS; Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center; University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA., Flores MD; Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center; University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA., Zink S; Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center; University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA., Schibrowsky NA; Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center; University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA., Sawaya MR; Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center; University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA., Rodriguez JA; Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center; University of California, Los Angeles (UCLA); Los Angeles, CA 90095, USA. |
| المصدر: | BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 11. Date of Electronic Publication: 2023 Feb 11. |
| نوع المنشور: | Preprint |
| اللغة: | English |
| بيانات الدورية: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: | ALECT2 is a type of systemic amyloidosis caused by deposition of the leukocyte cell-derived chemotaxin-2 (LECT2) protein in the form of fibrils. In ALECT2, LECT2 fibril deposits can be found in the glomerulus, resulting in renal failure. Affected patients lack effective treatment options outside of renal transplant or dialysis. While the structure of LECT2 in its globular form has been determined by X-ray crystallography, structures of LECT2 amyloid fibrils remain unknown. Using single particle cryo-EM, we now find that human LECT2 forms robust twisting fibrils with canonical amyloid features. At their core, LECT2 fibrils contain two mating protofilaments, the ordered core of each protofilament spans residues 55-75 of the LECT2 sequence. The overall geometry of the LECT2 fibril displays features in line with other pathogenic amyloids. Its core is tightly packed and stabilized by a network of hydrophobic contacts and hydrogen-bonded uncharged polar residues, while its outer surface displays several charged residues. The robustness of LECT2 fibril cores is illustrated by their limited dissolution in 3M urea and their persistence after treatment with proteinase K. As such, the LECT2 fibril structure presents a potential new target for treatments against ALECT2. |
| التعليقات: | Update in: Structure. 2023 Aug 22;:. (PMID: 37657439) |
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| معلومات مُعتمدة: | R35 GM128867 United States GM NIGMS NIH HHS; T32 GM008496 United States GM NIGMS NIH HHS; U24 GM129541 United States GM NIGMS NIH HHS |
| تواريخ الأحداث: | Date Created: 20230217 Latest Revision: 20231103 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9934627 |
| DOI: | 10.1101/2023.02.08.527771 |
| PMID: | 36798409 |
| قاعدة البيانات: | MEDLINE |
| DOI: | 10.1101/2023.02.08.527771 |
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