http://www.cnr.it/ontology/cnr/individuo/prodotto/ID311171

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1 (Articolo in rivista)

Type

Articolo in rivista (Classe)
Prodotto della ricerca (Classe)

Label

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1 (Articolo in rivista) (literal)

Anno

2014-01-01T00:00:00+01:00 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi

10.1073/pnas.1401065111 (literal)

Alternative label

Heidarsson, Petur O.[ 1 ] ; Naqvi, Mohsin M.[ 2,3 ] ; Otazo, Mariela R.[ 2,4 ] ; Mossa, Alessandro[ 5,6 ] ; Kragelund, Birthe B.[ 1 ] ; Cecconi, Ciro[ 2,3 ] (2014)
Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1
in Proceedings of the National Academy of Sciences of the United States of America
(literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

Heidarsson, Petur O.[ 1 ] ; Naqvi, Mohsin M.[ 2,3 ] ; Otazo, Mariela R.[ 2,4 ] ; Mossa, Alessandro[ 5,6 ] ; Kragelund, Birthe B.[ 1 ] ; Cecconi, Ciro[ 2,3 ] (literal)

Pagina inizio

13069 (literal)

Pagina fine

13074 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url

http://www.scopus.com/inward/record.url?eid=2-s2.0-84907001202&partnerID=q2rCbXpz (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume

111 (literal)

Rivista

Proceedings of the National Academy of Sciences of the United States of America (Rivista)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo

36 (literal)

Note

Scopu (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

[ 1 ] Univ Copenhagen, Dept Biol, Struct Biol & NMR Lab, DK-2200 Copenhagen, Denmark [ 2 ] CNR, Inst Nanosci S3, I-41125 Modena, Italy [ 3 ] Univ Modena & Reggio Emilia, Dept Phys Informat & Math, I-41125 Modena, Italy [ 4 ] Ctr Appl Technol & Nucl Dev, Dept Phys, Havana, Cuba [ 5 ] Univ Bari, Dept Phys, I-70126 Bari, Italy [ 6 ] Ist Nazl Fis Nucl, Sez Bari, I-70126 Bari, Italy (literal)

Titolo

Direct single-molecule observation of calcium-dependent misfolding in human neuronal calcium sensor-1 (literal)

Abstract

Neurodegenerative disorders are strongly linked to protein misfolding, and crucial to their explication is a detailed understanding of the underlying structural rearrangements and pathways that govern the formation of misfolded states. Here we use singlemolecule optical tweezers to monitor misfolding reactions of the human neuronal calcium sensor-1, a multispecific EF-hand protein involved in neurotransmitter release and linked to severe neurological diseases. We directly observed two misfolding trajectories leading to distinct kinetically trapped misfolded conformations. Both trajectories originate from an on-pathway intermediate state and compete with native folding in a calcium-dependent manner. The relative probability of the different trajectories could be affected by modulating the relaxation rate of applied force, demonstrating an unprecedented real-time control over the free-energy landscape of a protein. Constant-force experiments in combination with hidden Markov analysis revealed the free-energy landscape of the misfolding transitions under both physiological and pathological calcium concentrations. Remarkably for a calcium sensor, we found that higher calcium concentrations increased the lifetimes of the misfolded conformations, slowing productive folding to the native state. We propose a rugged, multidimensional energy landscape for neuronal calcium sensor-1 and speculate on a direct link between protein misfolding and calcium dysregulation that could play a role in neurodegeneration. (literal)

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