A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior.
A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of β2-microglobulin (ΔN6) lacking the first six N-terminal residues. Here we perform a computational study on ΔN6, which provides clues to understand the amyloidogenicity of the full...
Guardado en:
| Autores principales: | , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2014
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/b39d67169f83433b9e75a3650129d7f7 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:b39d67169f83433b9e75a3650129d7f7 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:b39d67169f83433b9e75a3650129d7f72021-11-18T05:52:54ZA simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior.1553-734X1553-735810.1371/journal.pcbi.1003606https://doaj.org/article/b39d67169f83433b9e75a3650129d7f72014-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24809460/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of β2-microglobulin (ΔN6) lacking the first six N-terminal residues. Here we perform a computational study on ΔN6, which provides clues to understand the amyloidogenicity of the full-length β2-microglobulin. Contrary to the wild-type form, ΔN6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in ΔN6 amyloidogenesis.Sílvia G EstácioHeinrich KrobathDiogo Vila-ViçosaMiguel MachuqueiroEugene I ShakhnovichPatrícia F N FaíscaPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 10, Iss 5, p e1003606 (2014) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Biology (General) QH301-705.5 |
| spellingShingle |
Biology (General) QH301-705.5 Sílvia G Estácio Heinrich Krobath Diogo Vila-Viçosa Miguel Machuqueiro Eugene I Shakhnovich Patrícia F N Faísca A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior. |
| description |
A major component of ex vivo amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of β2-microglobulin (ΔN6) lacking the first six N-terminal residues. Here we perform a computational study on ΔN6, which provides clues to understand the amyloidogenicity of the full-length β2-microglobulin. Contrary to the wild-type form, ΔN6 is able to efficiently nucleate fibrillogenesis in vitro at physiological pH. This behavior is enhanced by a mild acidification of the medium such as that occurring in the synovial fluid of DRA patients. Results reported in this work, based on molecular simulations, indicate that deletion of the N-terminal hexapeptide triggers the formation of an intermediate state for folding and aggregation with an unstructured strand A and a native-like core. Strand A plays a pivotal role in aggregation by acting as a sticky hook in dimer assembly. This study further predicts that the detachment of strand A from the core is maximized at pH 6.2 resulting into higher aggregation efficiency. The structural mapping of the dimerization interface suggests that Tyr10, His13, Phe30 and His84 are hot-spot residues in ΔN6 amyloidogenesis. |
| format |
article |
| author |
Sílvia G Estácio Heinrich Krobath Diogo Vila-Viçosa Miguel Machuqueiro Eugene I Shakhnovich Patrícia F N Faísca |
| author_facet |
Sílvia G Estácio Heinrich Krobath Diogo Vila-Viçosa Miguel Machuqueiro Eugene I Shakhnovich Patrícia F N Faísca |
| author_sort |
Sílvia G Estácio |
| title |
A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior. |
| title_short |
A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior. |
| title_full |
A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior. |
| title_fullStr |
A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior. |
| title_full_unstemmed |
A simulated intermediate state for folding and aggregation provides insights into ΔN6 β2-microglobulin amyloidogenic behavior. |
| title_sort |
simulated intermediate state for folding and aggregation provides insights into δn6 β2-microglobulin amyloidogenic behavior. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2014 |
| url |
https://doaj.org/article/b39d67169f83433b9e75a3650129d7f7 |
| work_keys_str_mv |
AT silviagestacio asimulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT heinrichkrobath asimulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT diogovilavicosa asimulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT miguelmachuqueiro asimulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT eugeneishakhnovich asimulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT patriciafnfaisca asimulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT silviagestacio simulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT heinrichkrobath simulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT diogovilavicosa simulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT miguelmachuqueiro simulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT eugeneishakhnovich simulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior AT patriciafnfaisca simulatedintermediatestateforfoldingandaggregationprovidesinsightsintodn6b2microglobulinamyloidogenicbehavior |
| _version_ |
1718424750517125120 |