{"doi":"10.1021/bi5011249","title":"Cooperative Stabilization of Transthyretin by Clusterin and Diflunisal","abstract":null,"journal":"Biochemistry","year":2015,"id":663240,"datarank":0.4887144807032224,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.0,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":715926,"name":"Elena S. Klimtchuk","orcid":null,"position":1,"is_corresponding":false},{"id":530353,"name":"David C. Seldin","orcid":"0000-0003-0168-2333","position":2,"is_corresponding":false},{"id":271732,"name":"John L. Berk","orcid":"0000-0002-1768-2373","position":3,"is_corresponding":false},{"id":441251,"name":"Lawreen H. Connors","orcid":"0000-0002-4672-4296","position":4,"is_corresponding":false},{"id":1731517,"name":"Michael J. Greene","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Cooperative Stabilization of Transthyretin by Clusterin and Diflunisal","abstract":"The circulating protein transthyretin (TTR) can unfold, oligomerize, and form highly structured amyloid fibrils that are deposited in tissues, causing organ damage and disease. This pathogenic process is caused by a heritable TTR point mutation in cases of familial TTR-related amyloidosis or wild-type TTR in cases of age-associated amyloidosis (previously called senile systemic amyloidosis). The TTR amyloid cascade is hypothesized to begin with the dissociation of the TTR native tetrameric structure into folded but unstable monomeric TTR subunits. Unfolding of monomeric TTR initiates an oligomerization process leading to aggregation and fibril formation. Numerous proteostatic mechanisms for regulating the TTR amyloid cascade exist. Extracellular chaperones provide an innate defense against misfolded proteins. Clusterin (CLU), a plasma protein, has the capacity to recognize exposed hydrophobic regions of misfolded proteins, shielding them from aggregation. We have previously demonstrated that CLU is associated with the amyloid fibrils in cardiac tissues from patients with TTR amyloidosis. In this study, we have used tetrameric and monomeric TTR structural variants to determine the ability of CLU to inhibit TTR amyloid fibril formation. Using circular dichroism spectroscopy, we determined that CLU preferentially stabilizes monomeric TTR and generates increasingly stable conformations under acid stress. Moreover, studies using surface plasmon resonance showed a direct interaction of CLU with high-molecular weight TTR oligomers. The interactions of CLU with monomeric and aggregated TTR proceed in a cooperative manner in the presence of diflunisal, a small molecule drug used to stabilize TTR tetramers.","is_dataset_classified":null,"base_score":3.258096538021482,"endowment":3.258096538021482,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25478940","pmcid":"PMC4303310","openalex_id":"https://openalex.org/W2409005075","authors":[],"funders":[{"funder_name":"National Institute on Aging","grant_id":"RO1AG031804","title":null},{"funder_name":"NIA NIH HHS","grant_id":"R01 AG031804","title":null},{"funder_name":"National Institutes of Health","grant_id":"2R56AG031804-06A1","title":"Molecular mechanism of senile cardiac amyloidosis"},{"funder_name":"Young Family Amyloid Research Fund","grant_id":"","title":null},{"funder_name":"Gerry Foundation","grant_id":"","title":null}],"total_grants":5,"fwci":0.8287,"citation_percentile":0.73880671,"influential_citations":0,"citation_trend":[{"year":2015,"count":5},{"year":2017,"count":1},{"year":2018,"count":4},{"year":2019,"count":1},{"year":2020,"count":4},{"year":2021,"count":2},{"year":2022,"count":3},{"year":2023,"count":2},{"year":2024,"count":1},{"year":2025,"count":1},{"year":2026,"count":1}],"oa_status":"bronze","license":"publisher-specific-oa","oa_locations":[{"url":"https://pubs.acs.org/doi/pdf/10.1021/bi5011249","host_type":"journal"},{"url":"https://pubs.acs.org/doi/pdf/10.1021/bi5011249","host_type":"publisher"},{"url":"https://doi.org/10.1021/bi5011249","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25478940","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4303310","host_type":"repository"},{"url":"http://citeseerx.ist.psu.edu/viewdoc/summary?doi=10.1.1.795.9515","host_type":""},{"url":"https://europepmc.org/articles/PMC4303310","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC4303310?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.1021/bi5011249","host_type":""},{"url":"https://dx.doi.org/10.1021/bi5011249","host_type":""}],"fields_of_study":["Clusterin in disease pathology","Caveolin-1 and cellular processes","Amyloidosis: Diagnosis, Treatment, Outcomes","0301 basic medicine","0303 health sciences","03 medical and health sciences","Amyloid","Anti-Inflammatory Agents, Non-Steroidal","Clusterin","Diflunisal","Humans","Male","Mutation","Prealbumin","Protein Stability","Protein Structure, Secondary","Protein Unfolding","Recombinant Proteins"],"mesh_terms":["Amyloid","Anti-Inflammatory Agents, Non-Steroidal","Diflunisal","Humans","Male","Mutation","Prealbumin","Recombinant Proteins","Protein Structure, Secondary","Clusterin","Protein Stability","Protein Unfolding"],"keywords":["Transthyretin","Diflunisal","Chemistry","Amyloidosis","Thioflavin","Amyloid (mycology)","Fibril","Amyloid disease","Proteostasis","Protein folding","Clusterin","Biophysics","Circular dichroism","Monomer","Protein aggregation","Biochemistry","Serpin","Amyloid fibril","Biology","Alzheimer's disease","Gene","Internal medicine","Medicine","Endocrinology","Male","Amyloid","Protein Stability","Anti-Inflammatory Agents, Non-Steroidal","Protein Structure, Secondary","Recombinant Proteins","Mutation","Humans","Prealbumin","Protein Unfolding"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"gen"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-12T20:35:04.335634Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}