CODSWALLOP

Alpha-synuclein

Homo sapiens · seed P37840 · 140 aa · family defined as ≥30% identity to that seed · compiled 07 October 2026

CATH and SCOP identifiers come from the RCSB's own structure annotations, which the Domains panel already reads, so these are looked up rather than guessed at.

234Entries 234Entities 45Constructs 3Organisms 40Ligand-bound
1.30 ÅBest res.
3.05 ÅMedian res.

Every figure here is counted over the whole family rather than quoted from one entry.

The reference structure

9JE2, the structure every other member of this family is superposed onto. Rendered by the RCSB and embedded here: the live app shows an interactive viewport, which a document that fetches nothing cannot.

Rendered structure of 9JE2
9JE2 at the RCSB · open it in the 3D viewer

Which residues anyone has ever seen

How many of this family's constructs contain each residue of the seed. A trough is a stretch nobody has put in a construct, which is a construct-design answer rather than a disorder one.

170140231 constructs

Constructs, most-used first

45 distinct constructs across 234 entries. 74 polymer entities differ from the UniProt canonical sequence in some way, 0 carry a recognised expression tag and 2 carry a fusion partner.

"Differs from canonical" is not the same as "engineered". The canonical sequence is the full gene product, so a secreted protein whose structures all start after its signal peptide counts every one of them as different: lysozyme's most-used construct, residues 19–147 on 1,239 entities, is simply the mature protein. Read the construct column below for what was actually done, rather than this count.

EntitiesLengthBest (Å)Best entryWhat was made
155 140 1.93 9EUU matches the canonical sequence
10 140 2.31 8PJO E46K
8 140 2.39 9JC3 G51D, A53T
5 140 2.21 9CKK A53T
5 140 2.60 9K23 matches the canonical sequence
3 55 3.10 8ZLO residues 45-99; E46K
3 64 2.87 9W08 residues 37-100
3 140 2.90 9O9K H50Q
2 62 3.40 9JKE residues 37-98; G51D, A53T, K58W
2 63 2.85 9JI8 residues 37-99
2 99 2.90 8ZMY residues 1-98
2 140 2.30 9O9J G51D
2 140 3.36 9KAL G51D, A53T, E57A
1 20 1.72 8ZVY residues 121-140
1 22 residues 35-56
1 27 residues 1-26
1 61 3.80 9RZF residues 37-97; N87S
1 63 3.03 9W07 residues 36-98; Y39E, K45G, K58G
1 63 3.32 9JDK residues 37-99; G51D, A53T
1 65 2.70 7WO0 residues 35-99; A53T
1 65 3.40 7WNZ residues 36-100; A53T
1 65 3.43 9TPT residues 36-100; E83Q
1 67 3.18 10XU residues 35-101
1 69 3.30 9V7C residues 32-101; 1 internal deletion; L100G, G101A
1 90 4.80 8GF7 residues 7-96

Showing the 25 most-used of 45.

Positions people deliberately mutate

Columns where the wild-type residue still dominates but a real minority carries something else, which is a different question from "what varies across species".

A53T 13% G51D 8% E46K 6% K58N 3% L100M 3% N103G 2% A107Y 2% D121G 2% N122S 2% S87N 2% E57A 2% G7A 1% H50Q 1% V3A 1% M5R 1% K6T 1% L8V 1% A19D 1% K21A 1% A30S 1% Y39E 1% M1K 0% D2S 0% F4Q 0% S9I 0% K10N 0% K12A 0% E13S 0% G14R 0% V15R 0%

What it assembles into

Oligomeric stateChainsEntriesShare
hexameric6 73 31.2%
decameric10 63 26.9%
dodecameric12 32 13.7%
monomeric1 10 4.3%
trimeric3 10 4.3%
pentadecameric15 10 4.3%
octameric8 8 3.4%
pentameric5 5 2.1%

74 entries have the depositor's assembly corroborated by PISA, 155 carry the depositor's word alone and 2 were assigned by PISA where the depositor gave none. The middle figure is not a disagreement: PISA may have returned nothing or never run.

Domain architecture

Every source's own domains on the seed axis, one row each. They are not merged: Pfam, CATH, SCOP and InterPro disagree about boundaries, and a merged track would state a consensus none of them gave.

CATHHelix hairpin binSCOP2BSynucleinType 2 solute binding prot170140
DomainSourceSpan (seed)Chains
Helix hairpin binCATH 1.10.287.700 1–140 2
SynucleinSCOP2B 8044121 1–140 3
Type 2 solute binding protein-likeSCOP2B 8058187 34–140 2

What binds it

A1BGB A1BGB4 entries A1EFL A1EFL4 entries 1KI 1KI3 entries TFX TFX3 entries IZV IZV3 entries NAG NAG3 entries V79 V792 entries IZ8 IZ82 entries IZM IZM1 entries 59P 59P1 entries 3LS 3LS1 entries Y9W Y9W1 entries
ComponentClassNameEntriesBest (Å)
A1BGBligand 2-(4-Benzyl-1-Oxophthalazin-2(1h)-Yl)-N-(2,6-Dimethylphenyl)acet 4 2.80
A1EFLligand (2~{R})-1-Fluoranyl-3-[[2-[(~{E})-2-[5-[6-(Methylamino)pyridin-3 4 2.60
CUion Copper (Ii) Ion 3
1KIligand 2-Bromanyl-4-[(~{E})-2-[6-[2-(2-Fluoranylethoxy)ethyl-Methyl-Ami 3 2.60
TFXligand 2-[4-(Dimethylamino)phenyl]-3,6-Dimethyl-1,3-Benzothiazol-3-Ium 3 2.90
IZVligand 2-[4-(Methylamino)phenyl]-1,3-Benzothiazol-6-Ol 3 2.80
NAGcofactor 2-Acetamido-2-Deoxy-Beta-D-Glucopyranose 3 3.10
CLion Chloride Ion 3 1.72
SO4ion Sulfate Ion 2 1.30
GOLcryoprotectant Glycerol 2 1.30
V79ligand Copper;trisodium;18-(2-Carboxylatoethyl)-20-(Carboxylatomethyl)- 2 2.50
IZ8ligand 4-Azanyl-6-[[4-[4-[(~{E})-(8-Azanyl-1-Oxidanyl-5,7-Disulfo-Napht 2 2.60
IZMligand 5-[(~{E})-2-(6-Methoxy-1,3-Benzoxazol-2-Yl)ethenyl]-~{N},~{N}-Di 1 2.80
59Pligand 3,3'-{[1,1'-Biphenyl]-4,4'-Diylbis[(E)-Diazene-2,1-Diyl]}bis(4-A 1 3.00
3LSligand 3''',4'-Bis(Carboxymethyl)-2,2':5',2'':5'',2''':5''',2''''-Quinq 1 2.70
Y9Wligand 2-[(~{E})-4-[6-(Methylamino)pyridin-3-Yl]but-1-En-3-Ynyl]-1,3-Be 1 3.00
KDHligand (2r,3r)-5,7-Dihydroxy-2-(3,4,5-Trihydroxyphenyl)-3,4-Dihydro-2h- 1 3.10
A1L13ligand ~{N},~{N}-Dimethyl-4-(6-Methyl-1,3-Benzothiazol-2-Yl)aniline 1 3.40
7TTligand Tetraphosphate 1 3.10
A1EFKligand 2-[(4~{E})-4-[(~{E})-3-(3-Methyl-1,3-Benzothiazol-2-Yl)prop-2-En 1 2.90

How it crystallises

Parsed from the free text 4 depositors typed into _exptl_crystal_grow.pdbx_details, out of 4 entries that recorded anything at all. Median pH 8.0 (range 8.0 to 9.0).

Precipitants

Ammonium sulfate × PEG ×

Buffers

Citrate × Tris ×

Which entries to trust

230 entries carry a wwPDB validation report: 194 clean, 28 worth a check and 8 with something to explain. Median clashscore 8.55, median RSRZ outliers 3.85%, median R-free minus R-work 0.043. 230 have released structure factors.

Across species

OrganismEntriesBest (Å)Ligand-boundSeed covered
Homo sapiens226 1.72 40 100%
Mus musculus5 2.60 0 100%
Escherichia coli2 1.30 0 35%
Unknown1 0 100%

Seed sequence

140 residues, numbered every ten. Every identity figure in this document is measured against this sequence.

active or binding site modified residue or glycosylation disulphide cysteine transmembrane or signal the 15 most-substituted positions

1MDVFMKGLSK AKEGVVAAAE KTKQGVAEAA GKTKEGVLYV GSKTKEGVVH GVATVAEKTK
61EQVTNVGGAV VTGVTAVAQK TVEGAGSIAA ATGFVKKDQL GKNEEGAPQE GILEDMPVDP
121DNEAYEMPSE EGYQDYEPEA

Sites are UniProt's curated features where the seed is a UniProt accession; the substituted positions are measured from this family's own alignment rather than annotated, and only the fifteen most substituted are marked: every position carrying a minority substitution would be most of the protein, because the family holds orthologues. A residue can carry more than one and is drawn with the first that applies, in the order of the key above.

Primary citations

One record per paper, not per entry.

YearCitation
2026 Formation of Condition-Dependent Alpha-Synuclein Fibril Strain in Artificial Cerebrospinal Fluid. Adv Sci doi:10.1002/advs.202505228
2026 Stochastic misfolding drives the emergence of distinct alpha-synuclein strains. Neuron doi:10.1016/j.neuron.2026.01.014
2025 Structural and functional insights into the nuclear role of Parkinson's disease-associated alpha-synuclein as a histone chaperone. Commun Biol doi:10.1038/s42003-025-08138-0
2025 Synthetic alpha-synuclein fibrils replicate in mice causing MSA-like pathology. Nature doi:10.1038/s41586-025-09698-1
2025 High-resolution Cryo-EM Structure Determination of a-Synuclein-A Prototypical Amyloid Fibril. Bio Protoc doi:10.21769/BioProtoc.5171
2025 Lewy-MSA hybrid fold drives distinct neuronal alpha-synuclein pathology. Commun Biol doi:10.1038/s42003-025-08355-7
2025 Fibril fuzzy coat is important for alpha-synuclein pathological transmission activity. Neuron doi:10.1016/j.neuron.2025.03.019
2025 Structural basis of a distinct alpha-synuclein strain that promotes tau inclusion in neurons. J.Biol.Chem. doi:10.1016/j.jbc.2025.108351
2025 Structural insight into binding of novel PET tracer MODAG-005 to lipidic alpha-Synuclein fibrils Biorxiv doi:10.1101/2025.04.21.649837
2025 A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features. Mol Neurodegener doi:10.1186/s13024-025-00889-y
2025 Leveraging bioorthogonal conjugation for alpha synuclein fibril surveillance. Biorxiv doi:10.1101/2025.09.12.675751
2025 A Novel alpha-Synuclein K58N Missense Variant in a Patient with Parkinson's Disease. Mov Disord doi:10.1002/mds.70030
2025 ATP Hydrolysis by alpha-Synuclein Amyloids is Mediated by Enclosing beta-Strand. Adv Sci doi:10.1002/advs.202508441
2025 Single-Molecule Insight Into alpha-Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds. Adv Sci doi:10.1002/advs.202416721
2025 Seed amplification of MSA alpha-synuclein aggregates preserves the biological and structural properties of brain-derived aggregates. Nat Commun doi:10.1038/s41467-025-66146-4
2025 Stepwise recruitment of chaperone Hsc70 by DNAJB1 produces ordered arrays primed for bursts of amyloid fibril disassembly. Commun Biol doi:10.1038/s42003-025-07906-2
2025 Cryo-EM structure of a novel alpha-synuclein filament subtype from multiple system atrophy. Febs Lett. doi:10.1002/1873-3468.15048
2025 Identical Seeding Characteristics and Cryo-EM Filament Structures in FTLD-Synuclein and Typical Multiple System Atrophy. Neuropathol Appl Neurobiol doi:10.1111/nan.70013
2025 Development of Nanomolar Affinity Miniprotein Inhibitors Targeting alpha-Synuclein Aggregation as Promising Therapeutic Agents for Parkinson's Disease Ccs Chem doi:10.31635/ccschem.025.202505587
2024 In cell NMR reveals cells selectively amplify and structurally remodel amyloid fibrils. Biorxiv doi:10.1101/2024.09.09.612142
2024 On the pH-dependence of alpha-synuclein amyloid polymorphism and the role of secondary nucleation in seed-based amyloid propagation. Elife doi:10.7554/eLife.93562
2024 Residues 2 to 7 of alpha-synuclein regulate amyloid formation via lipid-dependent and lipid-independent pathways. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.2315006121
2024 Phosphorylation and O-GlcNAcylation at the same alpha-synuclein site generate distinct fibril structures. Nat Commun doi:10.1038/s41467-024-46898-1
2024 Binding adaptability of chemical ligands to polymorphic alpha-synuclein amyloid fibrils. Proc.Natl.Acad.Sci.USA doi:10.1073/pnas.2321633121
2024 Different charged biopolymers induce alpha-synuclein to form fibrils with distinct structures. J.Biol.Chem. doi:10.1016/j.jbc.2024.107862
2024 Mouse alpha-synuclein fibrils are structurally and functionally distinct from human fibrils associated with Lewy body diseases. Sci Adv doi:10.1126/sciadv.adq3539
2024 Vaccination with structurally adapted fungal protein fibrils induces immunity to Parkinson's disease. Brain doi:10.1093/brain/awae061
2024 Structure-Toxicity Relationship in Intermediate Fibrils from alpha-Synuclein Condensates. J.Am.Chem.Soc. doi:10.1021/jacs.3c14703
2024 O-GlcNAc forces an alpha-synuclein amyloid strain with notably diminished seeding and pathology. Nat.Chem.Biol. doi:10.1038/s41589-024-01551-2
2024 Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue. Nat Commun doi:10.1038/s41467-024-46832-5
2023 New SNCA mutation and structures of alpha-synuclein filaments from juvenile-onset synucleinopathy. Acta Neuropathol doi:10.1007/s00401-023-02550-8
2023 Conformational change of alpha-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson's disease. Structure doi:10.1016/j.str.2022.11.013
2023 Structural Insights of Fe3+ Induced alpha-synuclein Fibrillation in Parkinson' Disease J.Mol.Biol. doi:10.1016/j.jmb.2022.167680
2023 Conformational Dynamics of an alpha-Synuclein Fibril upon Receptor Binding Revealed by Insensitive Nuclei Enhanced by Polarization Transfer-Based Solid-State Nuclear Magnetic Resonance and Cryo-Electron Microscopy. J.Am.Chem.Soc. doi:10.1021/jacs.2c10854
2023 Cryo-EM structure of amyloid fibril formed by alpha-synuclein hereditary A53E mutation reveals a distinct protofilament interface. J.Biol.Chem. doi:10.1016/j.jbc.2023.104566
2023 An N-terminal alpha-Synuclein fragment binds lipid vesicles to modulate lipid induced aggregation Cell Rep Phys Sci
2023 High-resolution structural information of membrane-bound alpha-synuclein provides insight into the MoA of the anti-Parkinson drug UCB0599 Proc. Natl. Acad. Sci. U. S. A. doi:10.1073/pnas.2201910120
2023 Structural and Dynamic Insights into -Synuclein Dimer Conformations doi:10.1016/j.str.2023.01.011
2022 Structures of alpha-synuclein filaments from human brains with Lewy pathology. Nature doi:10.1038/s41586-022-05319-3
2022 The 3D structure of lipidic fibrils of alpha-synuclein. Nat Commun doi:10.1038/s41467-022-34552-7