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

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

doi:10.1038/s41598-017-00036-8

Cited by 141 publications

(91 citation statements)

References 18 publications

(51 reference statements)

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“…Potential templates with lower, but still significant homology (85–98% confidence) were identified in bacterial insecticidal toxins from Bacillus thuringiensis and Alcaligensis faecalis ( Kelker et al. 2014 ; Yalpani et al. 2017 ) and in the fungal sphingomyelin-binding/toxic proteins nakanori ( Makino et al.…”

Section: Resultsmentioning

confidence: 99%

Piercing Fishes: Porin Expansion and Adaptation to Hematophagy in the Vampire Snail Cumia reticulata

Gerdol

Cervelli

Oliverio

et al. 2018

Molecular Biology and Evolution

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Cytolytic pore-forming proteins are widespread in living organisms, being mostly involved in both sides of the host–pathogen interaction, either contributing to the innate defense or promoting infection. In venomous organisms, such as spiders, insects, scorpions, and sea anemones, pore-forming proteins are often secreted as key components of the venom. Coluporins are pore-forming proteins recently discovered in the Mediterranean hematophagous snail Cumia reticulata (Colubrariidae), highly expressed in the salivary glands that discharge their secretion at close contact with the host. To understand their putative functional role, we investigated coluporins’ molecular diversity and evolutionary patterns. Coluporins is a well-diversified family including at least 30 proteins, with an overall low sequence similarity but sharing a remarkably conserved actinoporin-like predicted structure. Tracking the evolutionary history of the molluscan porin genes revealed a scattered distribution of this family, which is present in some other lineages of predatory gastropods, including venomous conoidean snails. Comparative transcriptomic analyses highlighted the expansion of porin genes as a lineage-specific feature of colubrariids. Coluporins seem to have evolved from a single ancestral porin gene present in the latest common ancestor of all Caenogastropoda, undergoing massive expansion and diversification in this colubrariid lineage through repeated gene duplication events paired with widespread episodic positive selection. As for other parasites, these findings are congruent with a “one-sided arms race,” equipping the parasite with multiple variants in order to broaden its host spectrum. Overall, our results pinpoint a crucial adaptive role for coluporins in the evolution of the peculiar trophic ecology of vampire snails.

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Section: Resultsmentioning

confidence: 99%

Piercing Fishes: Porin Expansion and Adaptation to Hematophagy in the Vampire Snail Cumia reticulata

Gerdol

Cervelli

Oliverio

et al. 2018

Molecular Biology and Evolution

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“…For example, both Cys and Ser [47], but not Gln, are known targets for post-translational protein palmitoylation, which anchors proteins to cellular membranes [48]. The palmitoylation of Cys residues in another protein, cysteine string protein α, is essential for protein aggregation and is associated with the neurodegenerative disease adult-onset neuronal ceroid lipofuscinosis [49]. Therefore, post-translational modification of polySer and polyCys, but not polyGln, may lead to protein interactions that drive protein aggregation in ways that are distinct from polyGln.…”

Section: Polycys and Polyser: Weakly Toxic Ran Productsmentioning

confidence: 99%

PolyQ-independent toxicity associated with novel translational products from CAG repeat expansions

2020

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Expanded CAG nucleotide repeats are the underlying genetic cause of at least 14 incurable diseases, including Huntington's disease (HD). The toxicity associated with many CAG repeat expansions is thought to be due to the translation of the CAG repeat to create a polyQ protein, which forms toxic oligomers and aggregates. However, recent studies show that HD CAG repeats undergo a non-canonical form of translation called Repeat-associated non-AUG dependent (RAN) translation. RAN translation of the CAG sense and CUG antisense RNAs produces six distinct repeat peptides: polyalanine (polyAla, from both CAG and CUG repeats), polyserine (polySer), polyleucine (polyLeu), polycysteine (polyCys), and polyglutamine (polyGln). The toxic potential of individual CAG-derived RAN polypeptides is not well understood. We developed pure C. elegans protein models for each CAG RAN polypeptide using codon-varied expression constructs that preserve RAN protein sequence but eliminate repetitive CAG/CUG RNA. While all RAN polypeptides formed aggregates, only polyLeu was consistently toxic across multiple cell types. In GABAergic neurons, which exhibit significant neurodegeneration in HD patients, codon-varied (Leu) 38 , but not (Gln) 38 , caused substantial neurodegeneration and motility defects. Our studies provide the first in vivo evaluation of CAG-derived RAN polypeptides in a multicellular model organism and suggest that polyQ-independent mechanisms, such as RAN-translated polyLeu peptides, may have a significant pathological role in CAG repeat expansion disorders.

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“…It is present in archaea and bacteria, mostly as monomeric proteins with two CDGSH domains [14, 31]. It has been suggested that the gene duplication that resulted in the eventual formation of mNT and NAF-1 in humans occurred around the time when vertebrates began to appear on Earth [31].…”

Section: Prefacementioning

confidence: 99%

The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease

et al. 2018

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NEET proteins comprise a new class of [2Fe-2S] cluster proteins. In human, three genes encode for NEET proteins: cisd1 encodes mitoNEET (mNT), cisd2 encodes the Nutrient-deprivation autophagy factor-1 (NAF-1) and cisd3 encodes MiNT (Miner2). These recently discovered proteins play key roles in many processes related to normal metabolism and disease. Indeed, NEET proteins are involved in iron, Fe-S, and reactive oxygen homeostasis in cells and play an important role in regulating apoptosis and autophagy. mNT and NAF-1 are homodimeric and reside on the outer mitochondrial membrane. NAF-1 also resides in the membranes of the ER associated mitochondrial membranes (MAM) and the ER. MiNT is a monomer with distinct asymmetry in the molecular surfaces surrounding the clusters. Unlike its paralogs mNT and NAF-1, it resides within the mitochondria. NAF-1 and mNT share similar backbone folds to the plant homodimeric NEET protein (At-NEET), while MiNT’s backbone fold resembles a bacterial MiNT protein. Despite the variation of amino acid composition among these proteins, all NEET proteins retained their unique CDGSH domain harboring their unique 3Cys:1His [2Fe-2S] cluster coordination through evolution. The coordinating exposed His was shown to convey the lability to the NEET proteins’ [2Fe-2S] clusters. In this minireview, we discuss the NEET fold and its structural elements. Special attention is given to the unique lability of the NEETs’ [2Fe-2S] cluster and the implication of the latter to the NEET proteins’ cellular and systemic function in health and disease.Graphical abstract

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

Cited by 141 publications

References 18 publications

Piercing Fishes: Porin Expansion and Adaptation to Hematophagy in the Vampire Snail Cumia reticulata

Piercing Fishes: Porin Expansion and Adaptation to Hematophagy in the Vampire Snail Cumia reticulata

PolyQ-independent toxicity associated with novel translational products from CAG repeat expansions

The unique fold and lability of the [2Fe-2S] clusters of NEET proteins mediate their key functions in health and disease

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