Dataset Information

The synucleins.

ABSTRACT: SUMMARY:Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors. The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. All synucleins have in common a highly conserved alpha-helical lipid-binding motif with similarity to the class-A2 lipid-binding domains of the exchangeable apolipoproteins. Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity with plant 'late-embryo-abundant' proteins. The alpha- and beta-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals. The gamma-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression. Normal cellular functions have not been determined for any of the synuclein proteins, although some data suggest a role in the regulation of membrane stability and/or turnover. Mutations in alpha-synuclein are associated with rare familial cases of early-onset Parkinson's disease, and the protein accumulates abnormally in Parkinson's disease, Alzheimer's disease, and several other neurodegenerative illnesses. The current challenge is to understand the normal cellular function of these proteins and how they might contribute to the development of human disease.

SUBMITTER: George JM

PROVIDER: S-EPMC150459 | biostudies-literature | 2002

REPOSITORIES: biostudies-literature

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The synucleins.

George Julia M JM

Genome biology 20011220 1

<h4>Summary</h4>Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors. The family includes three known proteins: alpha-synuclein, beta-synuclein, and gamma-synuclein. All synucleins have in common a highly conserved alpha-helical lipid-binding motif with similarity to the class-A2 lipid-binding domains of the exchangeable apolipoproteins. Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity ...[more]

PMID: 11806835

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Project description:In this work, we explored the intrinsic disorder status of the three members of the synuclein family of proteins-α-, β-, and γ-synucleins-and showed that although all three human synucleins are highly disordered, the highest levels of disorder are observed in γ-synuclein. Our analysis of the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members revealed that the pathological mutations A30P, E46K, H50Q, A53T, and A53E associated with the early onset of Parkinson's disease caused some increase in the local disorder propensity of human α-synuclein. A comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluation of their levels of intrinsic disorder using a set of commonly used bioinformatics tools revealed that, irrespective of their origin, all members of the synuclein family analyzed in this study were predicted to be highly disordered proteins, indicating that their intrinsically disordered nature represents an evolutionary conserved and therefore functionally important feature. A detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members utilizing a set of commonly used disorder analysis tools showed that the human α-synuclein interactome has relatively higher levels of intrinsic disorder as compared with the interactomes of human β- and γ- synucleins and revealed that, relative to the β- and γ-synuclein interactomes, α-synuclein interactors are involved in a much broader spectrum of highly diversified functional pathways. Although proteins interacting with three human synucleins were characterized by highly diversified functionalities, this analysis also revealed that the interactors of three human synucleins were involved in three common functional pathways, such as the synaptic vesicle cycle, serotonergic synapse, and retrograde endocannabinoid signaling. Taken together, these observations highlight the critical importance of the intrinsic disorder of human synucleins and their interactors in various neuronal processes.

Project description:Abnormal ?-synuclein aggregates are hallmarks of a number of neurodegenerative diseases. Alpha synuclein and ?-synucleins are susceptible to post-translational modification as isoaspartate protein damage, which is regulated in vivo by the action of the repair enzyme protein L-isoaspartyl O-methyltransferase (PIMT). We aged in vitro native ?-synuclein, the ?-synuclein familial mutants A30P and A53T that give rise to Parkinsonian phenotypes, and ?-synuclein, at physiological pH and temperature for a time course of up to 20 days. Resolution of native ?-synuclein and ?-synuclein by two dimensional techniques showed the accumulation of a number of post-translationally modified forms of both proteins. The levels of isoaspartate formed over the 20 day time course were quantified by exogenous methylation with PIMT using S-Adenosyl-L-[(3)H-methyl]methionine as a methyl donor, and liquid scintillation counting of liberated (3)H-methanol. All ?-synuclein proteins accumulated isoaspartate at ?1% of molecules/day, ?20 times faster than for ?-synuclein. This disparity between rates of isoaspartate was confirmed by exogenous methylation of synucleins by PIMT, protein resolution by one-dimensional denaturing gel electrophoresis, and visualisation of (3)H-methyl esters by autoradiography. Protein silver staining and autoradiography also revealed that ?-synucleins accumulated stable oligomers that were resistant to denaturing conditions, and which also contained isoaspartate. Co-incubation of approximately equimolar ?-synuclein with ?-synuclein resulted in a significant reduction of isoaspartate formed in all ?-synucleins after 20 days of ageing. Co-incubated ?- and ?-synucleins, or ?, or ? synucleins alone, were resolved by non-denaturing size exclusion chromatography and all formed oligomers of ?57.5 kDa; consistent with tetramerization. Direct association of ?-synuclein with ?-synuclein in column fractions or from in vitro ageing co-incubations was demonstrated by their co-immunoprecipitation. These results provide an insight into the molecular differences between ?- and ?-synucleins during ageing, and highlight the susceptibility of ?-synuclein to protein damage, and the potential protective role of ?-synuclein.

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The synucleins.

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The synucleins.

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