A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis

Cinta Diez Ardanuy, Jennifer Greaves, Kevin R. Munro, Nicholas C.O. Tomkinson, Luke H. Chamberlain

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Autosomal-dominant adult-onset neuronal cero id lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSP α ). The disease- causing mutations, which result in substituti on of leucine-115 with an arginine (L115R) or deletion of the neig hbouring leucine-116 ( Δ L116) in the cysteine-string domain cause CSP α to form high molecular weight SDS-resistant aggregates, which are also present in post- mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-str ing domain, however the regions of the mutant proteins that drive aggregatio n have not been determined. The importance of specific residues in the cysteine-string domain was in vestigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of ANCL CSP α mutants. Interestingly, palmitoylated monomers of ANCL CSP α mutants were shown to be short-lived compared with wild-type CSP α, suggesting that the mutants eith er have a faster rate of depalmitoylation or that they are consumed in a time-dependent manner into high molecular weight aggregates. These findings provide new insight into the features of CSP α that promote aggregation in the presence of L115R/ Δ L116 mutations and reveal a change in the lifetime of palmitoyla ted monomers of the mutant proteins.
LanguageEnglish
Article number10
Number of pages10
JournalScientific Reports
DOIs
Publication statusPublished - 31 Jan 2017

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Neuronal Ceroid-Lipofuscinoses
1-(3'-methoxy-4'-hydroxy-phenyl)-6,7-dihydroxyisochroman
Cysteine
Mutant Proteins
Leucine
Mutation
Molecular Weight
Lipoylation
Arginine
cysteine string protein
Brain
Genes

Keywords

  • neuronal ceroid lipofuscinosis
  • mutations
  • mutant proteins

Cite this

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title = "A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis",
abstract = "Autosomal-dominant adult-onset neuronal cero id lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSP α ). The disease- causing mutations, which result in substituti on of leucine-115 with an arginine (L115R) or deletion of the neig hbouring leucine-116 ( Δ L116) in the cysteine-string domain cause CSP α to form high molecular weight SDS-resistant aggregates, which are also present in post- mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-str ing domain, however the regions of the mutant proteins that drive aggregatio n have not been determined. The importance of specific residues in the cysteine-string domain was in vestigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of ANCL CSP α mutants. Interestingly, palmitoylated monomers of ANCL CSP α mutants were shown to be short-lived compared with wild-type CSP α, suggesting that the mutants eith er have a faster rate of depalmitoylation or that they are consumed in a time-dependent manner into high molecular weight aggregates. These findings provide new insight into the features of CSP α that promote aggregation in the presence of L115R/ Δ L116 mutations and reveal a change in the lifetime of palmitoyla ted monomers of the mutant proteins.",
keywords = "neuronal ceroid lipofuscinosis, mutations, mutant proteins",
author = "{Diez Ardanuy}, Cinta and Jennifer Greaves and Munro, {Kevin R.} and Tomkinson, {Nicholas C.O.} and Chamberlain, {Luke H.}",
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T1 - A cluster of palmitoylated cysteines are essential for aggregation of cysteine-string protein mutants that cause neuronal ceroid lipofuscinosis

AU - Diez Ardanuy, Cinta

AU - Greaves, Jennifer

AU - Munro, Kevin R.

AU - Tomkinson, Nicholas C.O.

AU - Chamberlain, Luke H.

PY - 2017/1/31

Y1 - 2017/1/31

N2 - Autosomal-dominant adult-onset neuronal cero id lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSP α ). The disease- causing mutations, which result in substituti on of leucine-115 with an arginine (L115R) or deletion of the neig hbouring leucine-116 ( Δ L116) in the cysteine-string domain cause CSP α to form high molecular weight SDS-resistant aggregates, which are also present in post- mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-str ing domain, however the regions of the mutant proteins that drive aggregatio n have not been determined. The importance of specific residues in the cysteine-string domain was in vestigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of ANCL CSP α mutants. Interestingly, palmitoylated monomers of ANCL CSP α mutants were shown to be short-lived compared with wild-type CSP α, suggesting that the mutants eith er have a faster rate of depalmitoylation or that they are consumed in a time-dependent manner into high molecular weight aggregates. These findings provide new insight into the features of CSP α that promote aggregation in the presence of L115R/ Δ L116 mutations and reveal a change in the lifetime of palmitoyla ted monomers of the mutant proteins.

AB - Autosomal-dominant adult-onset neuronal cero id lipofuscinosis (ANCL) is caused by mutation of the DNAJC5 gene encoding cysteine string protein alpha (CSP α ). The disease- causing mutations, which result in substituti on of leucine-115 with an arginine (L115R) or deletion of the neig hbouring leucine-116 ( Δ L116) in the cysteine-string domain cause CSP α to form high molecular weight SDS-resistant aggregates, which are also present in post- mortem brain tissue from patients. Formation and stability of these mutant aggregates is linked to palmitoylation of the cysteine-str ing domain, however the regions of the mutant proteins that drive aggregatio n have not been determined. The importance of specific residues in the cysteine-string domain was in vestigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of ANCL CSP α mutants. Interestingly, palmitoylated monomers of ANCL CSP α mutants were shown to be short-lived compared with wild-type CSP α, suggesting that the mutants eith er have a faster rate of depalmitoylation or that they are consumed in a time-dependent manner into high molecular weight aggregates. These findings provide new insight into the features of CSP α that promote aggregation in the presence of L115R/ Δ L116 mutations and reveal a change in the lifetime of palmitoyla ted monomers of the mutant proteins.

KW - neuronal ceroid lipofuscinosis

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