DP00070: Alpha-synucleinFASTA viewXML view

General information
DisProt:DP00070
Name:Alpha-synuclein
Synonym(s):SYUA_HUMAN
Non-A beta component of AD amyloid
Non-A4 component of amyloid precursor
NACP
SNCA
NACP140 [Isoform 1]
First appeared in release:Release 1.0 (08/01/2003)
UniProt:P37840-1
UniGene:Hs.21374
SwissProt: SYUA_HUMAN
TrEMBL:  
NCBI (GI): 586067
Source organism:Homo sapiens (Human)
Sequence length:140
Percent disordered:100%
Homologues: 


Native sequence

        10         20         30         40         50         60
         |          |          |          |          |          |
MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK - 60
EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP - 120
DNEAYEMPSE EGYQDYEPEA



Functional narrative    

Alpha-synuclein plays a role in presynaptic signaling and control of membrane traffic through protein-protein interactions and polymerization. The entire protein (residues 1-140) are found to be natively unfolded as a mixture of rapidly equilibrating conformers. SNCA is concentrated in the presynaptic nerve terminals of the brain, primarily the regions of the olfactory bulb, frontal cortex, striatum, and hippocampus, with lower concentrations being found in most tissues, excluding the liver. It interacts with phospholipase D and histones to form aggregates, but exists as a soluble monomer found in the cytoplasm and nucleus. These filamentous aggregates are the major non-amyloid component of intracellular inclusions in several neurodegenerative diseases, including Parkinson's disease type 1, Alzheimer's, and has been found to be responsible for neuroaxonal dystrophy associated with Hallervorden-Spatz syndrome.

Region 1: 1-140

Map of ordered and disordered regions







Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.


Region 1
Type:Disordered - Extended
Name: 
Location:1 - 140
Length:140
Region sequence:

MDVFMKGLSKAKEGVVAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEGVVHGVATVAEKTK
EQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQLGKNEEGAPQEGILEDMPVDP
DNEAYEMPSEEGYQDYEPEA

Modification type: Isoform
Native
PDB:  
Structural/functional type: Relationship to function unknown
Functional classes: Molecular assembly
Functional subclasses: Metal binding
Polymerization
Protein-protein binding
Detection methods:
  1. Circular dichroism (CD) spectroscopy, far-UV (pH: 7.5; Tris (buffer) 10 mM)

  2. Fourier transform infrared spectroscopy (FTIR), aka infrared spectroscopy) (Calcium fluoride (solution cell) 0.05 mm; NACP (per mL of D2O) 4 mg)

  3. Nuclear magnetic resonance (NMR) (pH: 7.4; H2O/2H2O (90%/10%); Na2HPO4 10 mM; NaCl 100 mM)
References:
  1. Bussell R Jr, Eliezer D. "Residual structure and dynamics in Parkinson's disease-associated mutants of alpha-synuclein." J Biol Chem. 2001; 276(49): 45996-6003. PubMed: 11590151

  2. Eliezer D, Kutluay E, Bussell R Jr, Browne G. "Conformational properties of alpha-synuclein in its free and lipid-associated states." J Mol Biol. 2001; 307(4): 1061-73. PubMed: 11286556

  3. Nielsen, M. S. Vorum, H. Lindersson, E. Jensen, P. H. "Ca2+ binding to alpha-synuclein regulates ligand binding and oligomerization." J Biol Chem. 2001; 276(25): 22680-22684. PubMed: 11312271

  4. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT Jr. "NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded." Biochemistry. 1996; 35(43): 13709-13715. PubMed: 8901511
Comments:
This region is composed of an N-terminal membrane anchoring region (residues 1 - 60), the central hydrophobic/amyloidogenic NAC region (residues 61-95), and a C-terminal acidic region (residues 96-140) that is inhibitory to amyloid formation. Amyloid formation may be the result of both phosphorylation of Ser129 and metal binding in the C-terminal region. When this occurs, residues 36 - 99 take on a cross-beta sheet structure characteristic of most amyloids, while the N- and C-termini remain statically and dynamically disordered, respectively.


References

  1. Allison JR, Varnai P, Dobson CM, Vendruscolo M. "Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements." J Am Chem Soc. 2009; 131(51): 18314-26. PubMed: 20028147

  2. Frimpong AK, Abzalimov RR, Uversky VN, Kaltashov IA. "Characterization of intrinsically disordered proteins with electrospray ionization mass spectrometry: Conformational heterogeneity of alpha-synuclein." Proteins. 2009. PubMed: 19847913

  3. Lee JC, Lai BT, Kozak JJ, Gray HB, Winkler JR. "Alpha-synuclein tertiary contact dynamics." J Phys Chem B. 2007; 111(8): 2107-12. PubMed: 17279794

  4. P. Tompa. "Structural disorder in amyloid fibrils: its implication in dynamic interactions of proteins." FEBS J. 2009; 27 Aug. PubMed: 19712107

  5. Uversky VN. "A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders." J Biomol Struct Dyn. 2003; 21(2): 211-34. PubMed: 12956606

  6. Uversky VN, Li J, Fink AL. "Pesticides directly accelerate the rate of alpha-synuclein fibril formation: a possible factor in Parkinson's disease." FEBS Lett. 2001; 500(3): 105-8. PubMed: 11445065

  7. Zhou W, Long C, Reaney SH, Di Monte DA, Fink AL, Uversky VN. "Methionine oxidation stabilizes non-toxic oligomers of alpha-synuclein through strengthening the auto-inhibitory intra-molecular long-range interactions." Biochim Biophys Acta. 2009. PubMed: 20026206


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