Sandbox Reserved 1109

This Sandbox is Reserved from 25/11/2019, through 30/9/2020 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1091 through Sandbox Reserved 1115.

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Generalities

spinqualitylabelsall models 6flt, resolution 3.42Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Alpha-synuclein is a protein encoded by the SNCA gene in humans and belongs to the family of synuclein proteins that also consist of beta and gamma- synuclein. It is present in large quantities in the brain and in comparatively smaller quantities in other tissues in the body. Alpha-synuclein is mainly present at the presynaptic terminals in the neuronal mitochondria and comprises of 1% of total cytosolic protein in the nervous system. It is mainly related to neurodegenerative diseases in humans. Function Even though it is well known that the aggregation of this protein is related to neurodegenerative disorders, the regular function of the protein is not well understood. However, the literature suggests that there exists a strong genetic link between the protein and degeneration that arises from the loss of certain chaperone proteins, called presynaptic chaperone cysteine string proteins (CSPα). This loss of CSPα does not affect the transmission of the neuronal signals immediately, but progresses with time. Excessive expression of alpha-synuclein is noted to delay degeneration that happens due to loss of CSPα, thus giving alpha synuclein a chaperone like function where this protein works with the CSPα in assembly of the SNARE complex, which is a type of large protein complex that deals with the fusion synaptic vesicles with the neurons in the brain. Therefore it is said that the main function of the alpha-synuclein is to regulate the neurotransmitter release. Structure The alpha-synuclein (1-121) is about 14 kDa fibril constituted by two protofilaments of 121 residues . The presence of many ꞵ-sheet induce a Greek-key motif of 99 Å diameter . Indeed, There are 8 Beta-strands interrupted by glycines, between the residues 42 to about 102 . These glycines help the folding of the molecule by their small size. Two structures coincide thanks to the presence of hydrophobic (red) and hydrophilic(blue) regions. A hydrophobic intra-molecular core between the two protofilaments is formed by alanines, valines and one isoleucine. Residues from 54 to 75 form a hydrophilic channel which contains majority of threonines and glutamic acid. To stabilize the protein in an aqueous solution, there are solvent-exposed charged residues: Lysine and glutamic acid. Fibrils form by stacking a rod polymorph. It is a helix with a pitch of 920 Å. Disease Parkinson's disease (PD) is the most common neurodegenerative disorder affecting more than 10 Million Worldwide . One of the main characteristics of Neurodegenerative disorders is the loss of the protective capacity surrounding the neurons or the gain of the toxic proteins. The mechanism by which the neuronal damage occurs is due to specific mutations, or other alterations of the synaptic proteins. Recently, it has been found that α-synuclein protein is the main component of Lewy bodies and Lewy neurites which are defining pathological characteristics of all Parkinson's disease cases. . Mechanism of aggregation Parkinson's disease is characterized by the accumulation of Lewy bodies in the substantia nigra, a region in the midbrain responsible for motor control, where Lewy bodies contain a build-up of α-synuclein found within the cells that contribute to the disease However, it is important to know that the pathway discussed above is one of many hypotheses for the role of α-synuclein in Parkinson's Disease (PD). Relevance Besides being of key importance in reducing the degeneration caused due to the loss of CSPα, the alpha-synuclein is also believed to be related to various other proteins that regulate its activity. An example of this is the interaction of synuclein with synphilin that promotes its aggregation, the details of this interaction however are still not clear. Recent studies also suggest that a small protein GTPase rab3a is believed to be regulating the association of the protein to the membrane dependent on GTP, but the mechanism of this regulation is not unclear as the function of the alpha synuclein is not totally understood. Alpha-synuclein is also believed to have an impact on protein degradation, cytoskeletal interrelations and complex 1 inhibition in mitochondria inducing oxidative stress that results in neuronal death. It also plays an important role in regulation of dopamine neurotransmission. Therefore, owing to the role that this protein plays, especially in neurodegenerative disorders, various therapeutic measures related to this protein are being studied.

References

Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013). The function of α-synuclein. Neuron, 79(6), 1044–1066. doi:10.1016/j.neuron.2013.09.004 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866954/ Cold Spring Harb Perspect Med 2012;4:a009399, Stefanis L.a-Synuclein in Parkinson’s Disease . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281589/pdf/cshperspectmed-PKD-a009399.pdf UniProtKB - P37840 (SYUA_HUMAN) https://www.uniprot.org/uniprot/P37840