Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins.
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| Title: | Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins. |
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| Authors: | Borgia, Madeleine B., Borgia, Alessandro, Best, Robert B., Steward, Annette, Nettels, Daniel, Wunderlich, Bengt, Schuler, Benjamin, Clarke, Jane |
| Source: | Nature. 6/30/2011, Vol. 474 Issue 7353, p662-665. 4p. 1 Diagram, 3 Graphs. |
| Subjects: | Protein folding, Proteins, Fluorescence, Immunoglobulins, Magnetic domain, Ferromagnetic materials, Energy transfer, Resonance |
| Abstract: | A large range of debilitating medical conditions is linked to protein misfolding, which may compete with productive folding particularly in proteins containing multiple domains. Seventy-five per cent of the eukaryotic proteome consists of multidomain proteins, yet it is not understood how interdomain misfolding is avoided. It has been proposed that maintaining low sequence identity between covalently linked domains is a mechanism to avoid misfolding. Here we use single-molecule Förster resonance energy transfer to detect and quantify rare misfolding events in tandem immunoglobulin domains from the I band of titin under native conditions. About 5.5 per cent of molecules with identical domains misfold during refolding in vitro and form an unexpectedly stable state with an unfolding half-time of several days. Tandem arrays of immunoglobulin-like domains in humans show significantly lower sequence identity between neighbouring domains than between non-adjacent domains. In particular, the sequence identity of neighbouring domains has been found to be preferentially below 40 per cent. We observe no misfolding for a tandem of naturally neighbouring domains with low sequence identity (24 per cent), whereas misfolding occurs between domains that are 42 per cent identical. Coarse-grained molecular simulations predict the formation of domain-swapped structures that are in excellent agreement with the observed transfer efficiency of the misfolded species. We infer that the interactions underlying misfolding are very specific and result in a sequence-specific domain-swapping mechanism. Diversifying the sequence between neighbouring domains seems to be a successful evolutionary strategy to avoid misfolding in multidomain proteins. [ABSTRACT FROM AUTHOR] |
| Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 61980895 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Borgia%2C+Madeleine+B%2E%22">Borgia, Madeleine B.</searchLink><br /><searchLink fieldCode="AR" term="%22Borgia%2C+Alessandro%22">Borgia, Alessandro</searchLink><br /><searchLink fieldCode="AR" term="%22Best%2C+Robert+B%2E%22">Best, Robert B.</searchLink><br /><searchLink fieldCode="AR" term="%22Steward%2C+Annette%22">Steward, Annette</searchLink><br /><searchLink fieldCode="AR" term="%22Nettels%2C+Daniel%22">Nettels, Daniel</searchLink><br /><searchLink fieldCode="AR" term="%22Wunderlich%2C+Bengt%22">Wunderlich, Bengt</searchLink><br /><searchLink fieldCode="AR" term="%22Schuler%2C+Benjamin%22">Schuler, Benjamin</searchLink><br /><searchLink fieldCode="AR" term="%22Clarke%2C+Jane%22">Clarke, Jane</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Nature%22">Nature</searchLink>. 6/30/2011, Vol. 474 Issue 7353, p662-665. 4p. 1 Diagram, 3 Graphs. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Protein+folding%22">Protein folding</searchLink><br /><searchLink fieldCode="DE" term="%22Proteins%22">Proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Fluorescence%22">Fluorescence</searchLink><br /><searchLink fieldCode="DE" term="%22Immunoglobulins%22">Immunoglobulins</searchLink><br /><searchLink fieldCode="DE" term="%22Magnetic+domain%22">Magnetic domain</searchLink><br /><searchLink fieldCode="DE" term="%22Ferromagnetic+materials%22">Ferromagnetic materials</searchLink><br /><searchLink fieldCode="DE" term="%22Energy+transfer%22">Energy transfer</searchLink><br /><searchLink fieldCode="DE" term="%22Resonance%22">Resonance</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: A large range of debilitating medical conditions is linked to protein misfolding, which may compete with productive folding particularly in proteins containing multiple domains. Seventy-five per cent of the eukaryotic proteome consists of multidomain proteins, yet it is not understood how interdomain misfolding is avoided. It has been proposed that maintaining low sequence identity between covalently linked domains is a mechanism to avoid misfolding. Here we use single-molecule Förster resonance energy transfer to detect and quantify rare misfolding events in tandem immunoglobulin domains from the I band of titin under native conditions. About 5.5 per cent of molecules with identical domains misfold during refolding in vitro and form an unexpectedly stable state with an unfolding half-time of several days. Tandem arrays of immunoglobulin-like domains in humans show significantly lower sequence identity between neighbouring domains than between non-adjacent domains. In particular, the sequence identity of neighbouring domains has been found to be preferentially below 40 per cent. We observe no misfolding for a tandem of naturally neighbouring domains with low sequence identity (24 per cent), whereas misfolding occurs between domains that are 42 per cent identical. Coarse-grained molecular simulations predict the formation of domain-swapped structures that are in excellent agreement with the observed transfer efficiency of the misfolded species. We infer that the interactions underlying misfolding are very specific and result in a sequence-specific domain-swapping mechanism. Diversifying the sequence between neighbouring domains seems to be a successful evolutionary strategy to avoid misfolding in multidomain proteins. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1038/nature10099 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 4 StartPage: 662 Subjects: – SubjectFull: Protein folding Type: general – SubjectFull: Proteins Type: general – SubjectFull: Fluorescence Type: general – SubjectFull: Immunoglobulins Type: general – SubjectFull: Magnetic domain Type: general – SubjectFull: Ferromagnetic materials Type: general – SubjectFull: Energy transfer Type: general – SubjectFull: Resonance Type: general Titles: – TitleFull: Single-molecule fluorescence reveals sequence-specific misfolding in multidomain proteins. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Borgia, Madeleine B. – PersonEntity: Name: NameFull: Borgia, Alessandro – PersonEntity: Name: NameFull: Best, Robert B. – PersonEntity: Name: NameFull: Steward, Annette – PersonEntity: Name: NameFull: Nettels, Daniel – PersonEntity: Name: NameFull: Wunderlich, Bengt – PersonEntity: Name: NameFull: Schuler, Benjamin – PersonEntity: Name: NameFull: Clarke, Jane IsPartOfRelationships: – BibEntity: Dates: – D: 30 M: 06 Text: 6/30/2011 Type: published Y: 2011 Identifiers: – Type: issn-print Value: 00280836 Numbering: – Type: volume Value: 474 – Type: issue Value: 7353 Titles: – TitleFull: Nature Type: main |
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