Amyloid fiber formation (Homo sapiens)

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3061521, 259, 18, 19, 28154163, 454414222, 5, 8, 10, 12...44481422431, 521131, 52140, 4815, 40135Golgi lumenendoplasmic reticulum lumencytosolendosome lumenUBC(153-228) NAT8B UBC(305-380) HIST1H2BJ SIAH1 HIST1H3A SerumamyloidP-componentpentamer:Double-stranded DNAGGA3 UBB(153-228) BACE1UBC(77-152) APP(672-713) BACE1(22-45)UBC(305-380) HSPG2(22-4391) HIST1H4A APP(18-770)K33polyUb SIAH1GGA2 SIAH1, SIAH2:SNCAIPK6polyUb HIST1H2BH SNCAIP K63Ub-SNCAIPH2AFZ SNCA A30P GGA1,2,3UBB(77-152) USPX9:SNCAHIST2H2AA3 RPS27A(1-76) SIAH2 HIST1H2BB BACE1 deacetylaseHIST1H2BL HIST1H2BC SIAH2 APP(672-713)SIAH2 7K-BACE1HIST2H3A SIAH1,SIAH2:UBE2L6:UbiquitinAPP(714-770)Serum amyloidP-componenthomopentamerHIST1H3A HIST2H2AC HIST1H2BM SIAH2 CH3COO-BACE1(46-501) APP(672-713) Ub-SNCA BACE1(46-501)HIST1H2AJ UBA52 APP(712-770)Localized amyloid fibril main peptide chains 7K-BACE1HIST1H2BJ H2AFB1 GGA1 HIST1H2BA HIST1H2AB HIST1H2BM H2BFS SNCAIP:SNCAsHIST1H2BA Double-stranded DNA UBC(381-456) UBC(77-152) UBE2L6PARK2 USP9XBACE1PolyUb-SNCAIPUBC(1-76) UBC(229-304) SIAH1,SIAH2:UBE2L6:Ubiquitin:SNCAUBC(1-76) BACE1:GGA1,2,3Ub-SNCAUBC(457-532) H2AFX APCS(20-223) H2BFS Serum amyloid PdecamerSIAH1 UBC(457-532) UBA52 SNCAIP-1AUBC(609-684) Ca2+ UBC(609-684) HIST1H2BB K29polyUb UBC(533-608) SNCA A30P GAG K63polyUbLocalized amyloid fibril main peptide chains H3F3A Ca2+ SNCA SNCAIP UbiquitinH3F3A SNCAIP UBB(1-76) UBA52 UBC(77-152) HIST1H2AD UBE2L6 HIST1H2BO HIST1H2BK HIST1H2BH PARK2:SNCAIPSNCA USP9X:Ub-SNCAAPP(672-713),APP(672-711)HIST2H2AA3 SIAH1, SIAH2K11polyUb SIAH1:UBE2L6:Ub-SNCAFURINH2AFB1 SIAH1 HIST1H2AJ PolyUbHIST1H2BL UBC(229-304) GGA3 HIST1H2BK Double-stranded DNAand chromatinPARK2UBB(153-228) UBC(381-456) APP(672-713),APP(672-711)UBC(609-684) SNCA7K-BACE1(46-501)UBB(77-152) HIST1H2BD UBC(305-380) UBC(381-456) SNCAIPUBC(229-304) HIST3H2BB APP(672-711)Systemic amyloid fibril monomers H2AFX K48polyUb H2OSNCAsK27polyUb UBC(457-532) HIST1H2BD UBE2L6 HIST1H2BN HIST1H2BC UBB(1-76) HIST2H2BE UBC(153-228) HIST2H2AC Ca2+ HIST1H2BO USP9X HIST1H2AC Amyloid fibrilsCa2+UBB(153-228) APP(672-711) Double-stranded DNA APCS(20-223) Amyloid fibrilmonomersHIST1H2AD UBC(153-228) Amyloid fibril mainpeptide chainsUb-SNCA HIST1H2AB NAT8, 8BAPP(18-671)Ac-CoASIAH1 GAGSystemic amyloid fibril main peptide chains SNCA UBC(533-608) Systemic amyloid fibril main peptide chains HIST3H2BB K63polyUb SNCA RPS27A(1-76) APCS(20-223) BACE1(46-501)Ca2+ GGA1 UBB(1-76) HIST2H3A Localized amyloid fibril monomers HSPG2(22-4391)CoA-SHUBC(533-608) HIST1H4A H2AFZ HIST1H2BN UBC(1-76) USP9X GGA2 HIST1H2AC UBB(77-152) SIAH1 APCS(20-223)RPS27A(1-76) APCS(20-223) APP(672-711) UBE2L6 NAT8 HIST2H2BE 30730303730


Description

Amyloid is a term used to describe deposits of fibrillar proteins, typically extracellular. The abnormal accumulation of amyloid, amyloidosis, is a term associated with tissue damage caused by amyloid deposition, seen in numerous diseases including neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Amyloid deposits consist predominantly of amyloid fibrils, rigid, non-branching structures that form ordered assemblies, characteristically with a cross beta-sheet structure where the sheets run parallel to the direction of the fibril (Sawaya et al. 2007). Often the fibril has a left-handed twist (Nelson & Eisenberg 2006). At least 27 human proteins form amyloid fibrils (Sipe et al. 2010). Many of these proteins have non-pathological functions; the trigger that leads to abnormal aggregations differs between proteins and is not well understood but in many cases the peptides are abnormal fragments or mutant forms arising from polymorphisms, suggesting that the initial event may be aggregation of misfolded or unfolded peptides. Early studies of Amyloid-beta assembly led to a widely accepted model that assembly was a nucleation-dependent polymerization reaction (Teplow 1998) but it is now understood to be more complex, with multiple 'off-pathway' events leading to a variety of oligomeric structures in addition to fibrils (Roychaudhuri et al. 2008), though it is unclear whether these intermediate steps are required in vivo. An increasing body of evidence suggests that these oligomeric forms are primarily responsible for the neurotoxic effects of Amyloid-beta (Roychaudhuri et al. 2008), alpha-synuclein (Winner et al. 2011) and tau (Dance & Strobel 2009, Meraz-Rios et al. 2010). Amyloid oligomers are believed to have a common structural motif that is independent of the protein involved and not present in fibrils (Kayed et al. 2003). Conformation dependent, aggregation specific antibodies suggest that there are 3 general classes of amyloid oligomer structures (Glabe 2009) including annular structures which may be responsible for the widely reported membrane permeabilization effect of amyloid oligomers. Toxicity of amyloid oligomers preceeds the appearance of plaques in mouse models (Ferretti et al. 2011).
Fibrils are often associated with other molecules, notably heparan sulfate proteoglycans and Serum Amyloid P-component, which are universally associated and seem to stabilize fibrils, possibly by protecting them from degradation. View original pathway at:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114869view16:37, 25 January 2021ReactomeTeamReactome version 75
113315view11:38, 2 November 2020ReactomeTeamReactome version 74
112526view15:48, 9 October 2020ReactomeTeamReactome version 73
101438view11:31, 1 November 2018ReactomeTeamreactome version 66
100977view21:09, 31 October 2018ReactomeTeamreactome version 65
100513view19:42, 31 October 2018ReactomeTeamreactome version 64
100059view16:26, 31 October 2018ReactomeTeamreactome version 63
99611view15:00, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99221view12:44, 31 October 2018ReactomeTeamreactome version 62
93929view13:45, 16 August 2017ReactomeTeamreactome version 61
93515view11:25, 9 August 2017ReactomeTeamreactome version 61
88058view13:48, 25 July 2016MkutmonOntology Term : 'peptide and protein metabolic process' added !
88054view13:47, 25 July 2016ReactomeTeamReactome version 56
83437view12:25, 18 November 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
7K-BACE1(46-501)ProteinP56817 (Uniprot-TrEMBL)
7K-BACE1ProteinP56817 (Uniprot-TrEMBL)
APCS(20-223) ProteinP02743 (Uniprot-TrEMBL)
APCS(20-223)ProteinP02743 (Uniprot-TrEMBL)
APP(18-671)ProteinP05067 (Uniprot-TrEMBL)
APP(18-770)ProteinP05067 (Uniprot-TrEMBL)
APP(672-711) ProteinP05067 (Uniprot-TrEMBL)
APP(672-711)ProteinP05067 (Uniprot-TrEMBL)
APP(672-713) ProteinP05067 (Uniprot-TrEMBL)
APP(672-713), APP(672-711)ComplexR-HSA-6783330 (Reactome)
APP(672-713), APP(672-711)ComplexR-HSA-976800 (Reactome)
APP(672-713)ProteinP05067 (Uniprot-TrEMBL)
APP(712-770)ProteinP05067 (Uniprot-TrEMBL)
APP(714-770)ProteinP05067 (Uniprot-TrEMBL)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
Amyloid fibril monomersComplexR-HSA-977175 (Reactome)
Amyloid fibril main peptide chainsComplexR-HSA-977144 (Reactome)
Amyloid fibrilsComplexR-HSA-977084 (Reactome)
BACE1 deacetylaseR-HSA-5693080 (Reactome)
BACE1(22-45)ProteinP56817 (Uniprot-TrEMBL)
BACE1(46-501) ProteinP56817 (Uniprot-TrEMBL)
BACE1(46-501)ProteinP56817 (Uniprot-TrEMBL)
BACE1:GGA1,2,3ComplexR-HSA-5692928 (Reactome)
BACE1ProteinP56817 (Uniprot-TrEMBL)
CH3COO-MetaboliteCHEBI:15366 (ChEBI)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
Double-stranded DNA and chromatinComplexR-HSA-977589 (Reactome)
Double-stranded DNA MetaboliteCHEBI:16991 (ChEBI)
FURINProteinP09958 (Uniprot-TrEMBL)
GAG MetaboliteCHEBI:18085 (ChEBI)
GAGMetaboliteCHEBI:18085 (ChEBI)
GGA1 ProteinQ9UJY5 (Uniprot-TrEMBL)
GGA1,2,3ComplexR-HSA-5692940 (Reactome)
GGA2 ProteinQ9UJY4 (Uniprot-TrEMBL)
GGA3 ProteinQ9NZ52 (Uniprot-TrEMBL)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4A ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
HSPG2(22-4391) ProteinP98160 (Uniprot-TrEMBL)
HSPG2(22-4391)ProteinP98160 (Uniprot-TrEMBL)
K11polyUb R-HSA-3095921 (Reactome)
K27polyUb R-HSA-5689212 (Reactome)
K29polyUb R-HSA-5689192 (Reactome)
K33polyUb R-HSA-5689142 (Reactome)
K48polyUb R-HSA-912740 (Reactome)
K63Ub-SNCAIPProteinQ9Y6H5 (Uniprot-TrEMBL)
K63polyUb R-HSA-450152 (Reactome)
K63polyUbR-HSA-450152 (Reactome)
K6polyUb R-HSA-5689106 (Reactome)
Localized amyloid fibril main peptide chains R-HSA-976963 (Reactome) Amyloid is a term used to describe deposits of fibrillar proteins, typically extracellular. The abnormal accumulation of amyloid, amyloidosis, is a term associated with tissue damage caused by amyloid deposition, seen in numerous diseases including neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Amyloid deposits consist predominantly of amyloid fibrils, rigid, non-branching structures that form ordered assemblies, characteristically with a cross beta-sheet structure where the sheets run parallel to the direction of the fibril (Sawaya et al. 2007). Often the fibril has a left-handed twist (Nelson & Eisenberg 2006). At least 27 human proteins form amyloid fibrils (Sipe et al. 2010). Many of these proteins have non-pathological functions; the trigger that leads to abnormal aggregations differs between proteins and is not well understood but in many cases the peptides are abnormal fragments or mutant forms arising from polymorphisms, suggesting that the initial event may be aggregation of misfolded or unfolded peptides. Early studies of Amyloid-beta assembly led to a widely accepted model that assembly was a nucleation-dependent polymerization reaction (Teplow 1998) but it is now understood to be more complex, with multiple 'off-pathway' events leading to a variety of oligomeric structures in addition to fibrils (Roychaudhuri et al. 2008), though it is unclear whether these intermediate steps are required in vivo. An increasing body of evidence suggests that these oligomeric forms are primarily responsible for the neurotoxic effects of Amyloid-beta (Roychaudhuri et al. 2008), alpha-synuclein (Winner et al. 2011) and tau (Dance & Strobel 2009, Meraz-Rios et al. 2010). Amyloid oligomers are believed to have a common structural motif that is independent of the protein involved and not present in fibrils (Kayed et al. 2003). Conformation dependent, aggregation specific antibodies suggest that there are 3 general classes of amyloid oligomer structures (Glabe 2009) including annular structures which may be responsible for the widely reported membrane permeabilization effect of amyloid oligomers. Toxicity of amyloid oligomers preceeds the appearance of plaques in mouse models (Ferretti et al. 2011).
Fibrils are often associated with other molecules, notably heparan sulfate proteoglycans and Serum Amyloid P-component, which are universally associated and seem to stabilize fibrils, possibly by protecting them from degradation.
Localized amyloid fibril monomers R-HSA-977181 (Reactome)
NAT8 ProteinQ9UHE5 (Uniprot-TrEMBL)
NAT8, 8BComplexR-HSA-5692996 (Reactome)
NAT8B ProteinQ9UHF3 (Uniprot-TrEMBL)
PARK2 ProteinO60260 (Uniprot-TrEMBL)
PARK2:SNCAIPComplexR-HSA-5658565 (Reactome)
PARK2ProteinO60260 (Uniprot-TrEMBL)
PolyUb-SNCAIPProteinQ9Y6H5 (Uniprot-TrEMBL)
PolyUbComplexR-HSA-5689096 (Reactome)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SIAH1 ProteinQ8IUQ4 (Uniprot-TrEMBL)
SIAH1, SIAH2:SNCAIPComplexR-HSA-5658551 (Reactome)
SIAH1, SIAH2ComplexR-HSA-5667115 (Reactome)
SIAH1,SIAH2:UBE2L6:Ubiquitin:SNCAComplexR-HSA-5658558 (Reactome)
SIAH1,SIAH2:UBE2L6:UbiquitinComplexR-HSA-5658557 (Reactome)
SIAH1:UBE2L6:Ub-SNCAComplexR-HSA-5660743 (Reactome)
SIAH1ProteinQ8IUQ4 (Uniprot-TrEMBL)
SIAH2 ProteinO43255 (Uniprot-TrEMBL)
SNCA A30P ProteinP37840 (Uniprot-TrEMBL)
SNCA ProteinP37840 (Uniprot-TrEMBL)
SNCAIP ProteinQ9Y6H5 (Uniprot-TrEMBL)
SNCAIP-1AProteinQ9Y6H5-2 (Uniprot-TrEMBL)
SNCAIP:SNCAsComplexR-HSA-5658520 (Reactome)
SNCAIPProteinQ9Y6H5 (Uniprot-TrEMBL)
SNCAProteinP37840 (Uniprot-TrEMBL)
SNCAsComplexR-HSA-5658571 (Reactome)
Serum

amyloid P-component

pentamer:Double-stranded DNA		ComplexR-HSA-977223 (Reactome)
Serum amyloid

P-component

homopentamer		ComplexR-HSA-976776 (Reactome)
Serum amyloid P decamerComplexR-HSA-976787 (Reactome)
Systemic amyloid fibril main peptide chains R-HSA-976760 (Reactome) Amyloid is a term used to describe deposits of fibrillar proteins, typically extracellular. The abnormal accumulation of amyloid, amyloidosis, is a term associated with tissue damage caused by amyloid deposition, seen in numerous diseases including neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Amyloid deposits consist predominantly of amyloid fibrils, rigid, non-branching structures that form ordered assemblies, characteristically with a cross beta-sheet structure where the sheets run parallel to the direction of the fibril (Sawaya et al. 2007). Often the fibril has a left-handed twist (Nelson & Eisenberg 2006). At least 27 human proteins form amyloid fibrils (Sipe et al. 2010). Many of these proteins have non-pathological functions; the trigger that leads to abnormal aggregations differs between proteins and is not well understood but in many cases the peptides are abnormal fragments or mutant forms arising from polymorphisms, suggesting that the initial event may be aggregation of misfolded or unfolded peptides. Early studies of Amyloid-beta assembly led to a widely accepted model that assembly was a nucleation-dependent polymerization reaction (Teplow 1998) but it is now understood to be more complex, with multiple 'off-pathway' events leading to a variety of oligomeric structures in addition to fibrils (Roychaudhuri et al. 2008), though it is unclear whether these intermediate steps are required in vivo. An increasing body of evidence suggests that these oligomeric forms are primarily responsible for the neurotoxic effects of Amyloid-beta (Roychaudhuri et al. 2008), alpha-synuclein (Winner et al. 2011) and tau (Dance & Strobel 2009, Meraz-Rios et al. 2010). Amyloid oligomers are believed to have a common structural motif that is independent of the protein involved and not present in fibrils (Kayed et al. 2003). Conformation dependent, aggregation specific antibodies suggest that there are 3 general classes of amyloid oligomer structures (Glabe 2009) including annular structures which may be responsible for the widely reported membrane permeabilization effect of amyloid oligomers. Toxicity of amyloid oligomers preceeds the appearance of plaques in mouse models (Ferretti et al. 2011).
Fibrils are often associated with other molecules, notably heparan sulfate proteoglycans and Serum Amyloid P-component, which are universally associated and seem to stabilize fibrils, possibly by protecting them from degradation.
Systemic amyloid fibril monomers R-HSA-977105 (Reactome)
UBA52 ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2L6 ProteinO14933 (Uniprot-TrEMBL)
UBE2L6ProteinO14933 (Uniprot-TrEMBL)
USP9X ProteinQ93008 (Uniprot-TrEMBL)
USP9X:Ub-SNCAComplexR-HSA-5661158 (Reactome)
USP9XProteinQ93008 (Uniprot-TrEMBL)
USPX9:SNCAComplexR-HSA-5661162 (Reactome)
Ub-SNCA ProteinP37840 (Uniprot-TrEMBL)
Ub-SNCAProteinP37840 (Uniprot-TrEMBL)
UbiquitinComplexR-HSA-8862034 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
7K-BACE1(46-501)ArrowR-HSA-5693081 (Reactome)
7K-BACE1(46-501)R-HSA-5693092 (Reactome)
7K-BACE1ArrowR-HSA-5693001 (Reactome)
7K-BACE1ArrowR-HSA-5693071 (Reactome)
7K-BACE1R-HSA-5693071 (Reactome)
7K-BACE1R-HSA-5693081 (Reactome)
APCS(20-223)R-HSA-976723 (Reactome)
APP(18-671)ArrowR-HSA-5692495 (Reactome)
APP(18-770)R-HSA-5692495 (Reactome)
APP(672-711)ArrowR-HSA-5692495 (Reactome)
APP(672-713), APP(672-711)ArrowR-HSA-6783332 (Reactome)
APP(672-713), APP(672-711)R-HSA-6783332 (Reactome)
APP(672-713)ArrowR-HSA-5692495 (Reactome)
APP(712-770)ArrowR-HSA-5692495 (Reactome)
APP(714-770)ArrowR-HSA-5692495 (Reactome)
Ac-CoAR-HSA-5693001 (Reactome)
Amyloid fibril monomersR-HSA-977136 (Reactome)
Amyloid fibril main peptide chainsArrowR-HSA-977136 (Reactome)
Amyloid fibril main peptide chainsR-HSA-976734 (Reactome)
Amyloid fibrilsArrowR-HSA-976734 (Reactome)
BACE1 deacetylasemim-catalysisR-HSA-5693092 (Reactome)
BACE1(22-45)ArrowR-HSA-5693081 (Reactome)
BACE1(46-501)ArrowR-HSA-5693086 (Reactome)
BACE1(46-501)ArrowR-HSA-5693092 (Reactome)
BACE1(46-501)R-HSA-5692934 (Reactome)
BACE1(46-501)R-HSA-5693086 (Reactome)
BACE1:GGA1,2,3ArrowR-HSA-5692934 (Reactome)
BACE1:GGA1,2,3R-HSA-5692941 (Reactome)
BACE1ArrowR-HSA-5692941 (Reactome)
BACE1R-HSA-5693001 (Reactome)
BACE1mim-catalysisR-HSA-5692495 (Reactome)
CH3COO-ArrowR-HSA-5693092 (Reactome)
Ca2+R-HSA-976723 (Reactome)
CoA-SHArrowR-HSA-5693001 (Reactome)
Double-stranded DNA and chromatinR-HSA-977224 (Reactome)
FURINmim-catalysisR-HSA-5693081 (Reactome)
GAGR-HSA-976734 (Reactome)
GGA1,2,3ArrowR-HSA-5692941 (Reactome)
GGA1,2,3R-HSA-5692934 (Reactome)
H2OR-HSA-5693092 (Reactome)
HSPG2(22-4391)R-HSA-976734 (Reactome)
K63Ub-SNCAIPArrowR-HSA-5667111 (Reactome)
K63polyUbR-HSA-5667111 (Reactome)
NAT8, 8Bmim-catalysisR-HSA-5693001 (Reactome)
PARK2:SNCAIPArrowR-HSA-5658574 (Reactome)
PARK2:SNCAIPmim-catalysisR-HSA-5667111 (Reactome)
PARK2R-HSA-5658574 (Reactome)
PolyUb-SNCAIPArrowR-HSA-5667107 (Reactome)
PolyUbR-HSA-5667107 (Reactome)
R-HSA-5658092 (Reactome) Seven in absentia homolog 1 (SIAH1) and 2 (SIAH2) are E3 ubiquitin-protein ligases that mediate ubiquitination of a number of target proteins including Synphilin-1 (SNCAIP) (Nagano et al. 2003) and alpha-synuclein (Liani et al. 2004). They are inhibited by the 1A isoform of SNCAIP (Szargel et al. 2009). When ubiquitinated by SIAH1, SNCAIP is targetted for proteasomal degradation (Nagano et al. 2003).

Synphilin-1 (SNCAIP) is a presynaptic protein that associates with synaptic vesicles (Ribeiro et al. 2002). It is present in many types of cytoplasmic inclusions, where it colocalizes with alpha-synuclein. It is associated with Parkinson's Disease (PD) because it is an intrinsic component of Lewy bodies (Wakabayashi et al. 2000) and a mutation of the SNCAIP gene has been identified in some PD patients (Marx et al. 2003), suggesting that accumulation of synphilin-1 and its interaction with alpha-synuclein may be relevant for Lewy body formation in PD.

Synphilin-1 (SNCAIP) is ubiquitinated by several other E3 ubiquitin-ligases, including Parkin (Chung et al. 2001) and Dorfin (Ito et al. 2003).
R-HSA-5658104 (Reactome) Synphilin-1 (SNCAIP) binds alpha-synuclein (SNCAs) in vivo, which promotes the formation of Lewy body-like inclusions that are characteristic of Parkinson's Disease (Engelender et al. 1999, Kawamata et al. 2001). SNCAIP and PARK2 (Parkin) are found in the central core of a majority of Lewy Bodies in Parkinson's disease (Bandopadhyay et al. 2005).
R-HSA-5658496 (Reactome) Seven in absentia homolog 1 (SIAH1) and 2 (SIAH2) are E3 ubiquitin-protein ligases that mediates ubiquitination of a number of target proteins including Synphilin-1 (SNCAIP) (Nagano et al. 2003) and alpha-synuclein (SNCA) (Liani et al. 2004, Lee et al. 2008). Ubiquitination of SNCA by SIAH1 is disrupted by the Parkinson's Disease (PD)-linked A30P mutation but not by the A53T mutation. SIAH1 binds the E2 ubiquitin-conjugating enzyme UBE2L6 (UBCH8) (Lee et al. 2008). This facilitates the mono- and di-ubiquitination of SNCA in vivo, but does not target SNCA for proteasomal degradation, rather it promotes SNCA aggregation and enhances toxicity (Lee et al. 2008). Monoubiquitinated SNCA may work as a seed for aggregation (Engelender 2008) and recruit other PD-related proteins, such as SNCAIP and UCHL1.
R-HSA-5658574 (Reactome) Synphilin-1 (SNCAIP) is a presynaptic protein that associates with synaptic vesicles (Ribeiro et al. 2002). It is present in many types of cytoplasmic inclusions, where it colocalizes with alpha-synuclein (SNCA). It is associated with Parkinson's Disease (PD) because it is an intrinsic component of Lewy bodies (Wakabayashi et al. 2000) and a mutation of the SNCAIP gene has been identified in some PD patients (Marx et al. 2003), suggesting that accumulation of SNCAIP and its interaction with SNCA may be relevant for Lewy body formation in PD.

SNCAIP is ubiquitinated by several different E3 ubiquitin-ligases, including Parkin (PARK2). PARK2 overexpression with SNCAIP in cell culture leads to the formation of protein aggregates (Chung et al. 2001). PARK2 preferentially mediates the addition of lysine-63 (K63)-linked polyubiquitination of SNCAIP (Lim et al. 2005). This leads to SNCAIP degradation only at an unusually high PARK2 to SNCAIP ratio (Lim et al. 2005). K63-linked ubiquitination may be a signal that leads to the degradation of inclusions by autophagy when the ubiquitin-proteasome system is dysfunctional (Lin et al. 2005, Tan et al. 2008).
R-HSA-5660752 (Reactome) The deubiquitinase USP9X binds and deubiquitinates alpha-synuclein (SNCA) in vitro and in vivo, showing co-accumulation with SNCA in Lewy Bodies. Knockdown of USP9X expression in conditions of proteolytic inhibition leads to the accumulation of monoubiquitinated SNCA and increases the aggregation of SNCA into toxic inclusions, strengthening the connection between monoubiquitination, inclusion formation, and toxicity of SNCA. USP9X cytosolic levels are lower in Diffuse Lewy Body disease and Parkinson's Disease tissues, which may contribute to the accumulation and aggregation of monoubiquitinated SNCA (Rott et al. 2011).
R-HSA-5660753 (Reactome) SIAH1 transfers ubiquitin from UBE2L6 to SNCA, generating monoubiquitinated SNCA (Ub-SNCA) (Liani et al 2004, Rott et al. 2008, Lee et al. 2008). Monoubiquitination of SNCA promotes its aggregation in vitro and in vivo, which is toxic to cells. Lewy Bodies, a characteristic of Parkinson's Disease, contain monoubiquitinted SNCA deposits (Hasegawa et al. 2002). Mass spectrometry analysis demonstrates that SIAH monoubiquitinates alpha-synuclein at lysines 12, 21, and 23 (Rott et al. 2008).

Monoubiquitination is generally thought to lead to degradation via the lysosomal pathway (d'Azzo et al. 2005) but monoubiquitinated SNCA appears to be preferentially targeted for degradation by the proteasome (Rott et al. 2011).
R-HSA-5660757 (Reactome) SNCA is monoubiquitinated and under some circumstances released to accumulate in the cell. Alternatively Ub-SNCA may undergo further rounds of ubiquitination producing diubiquitinated or polyubiquitinated forms. The precise mechanism of release and subsequent further ubiquitination is unclear (Sadowski et al. 2011); the E3 ligase may remain bound to SNCA while the E2 ligase dissociates to be replaced by a Ubiquitin-associated replacement, or the E2/E3 complex may dissociate completely allowing a different E3 to bind the SNCA substrate.
R-HSA-5661157 (Reactome) The deubiquitinase USP9X binds and deubiquitinates alpha-synuclein (SNCA) in vitro and in vivo, showing co-accumulation with SNCA in Lewy Bodies. Knockdown of USP9X expression in conditions of proteolytic inhibition leads to the accumulation of monoubiquitinated SNCA and increases the aggregation of SNCA into toxic inclusions, strengthening the connection between monoubiquitination, inclusion formation, and toxicity of SNCA. USP9X cytosolic levels are lower in Diffuse Lewy Body disease and Parkinson's Disease tissues, which may contribute to the accumulation and aggregation of monoubiquitinated SNCA (Rott et al. 2011).
R-HSA-5661161 (Reactome) Following the removal of ubiquitin, SNCA is released by USP9X (Rott et al. 2011).
R-HSA-5667107 (Reactome) Seven in absentia homolog (SIAH1) and 2 (SIAH2) are E3 ubiquitin-protein ligases that mediate ubiquitination of a number of target proteins including Synphilin-1 (SNCAIP) (Nagano et al. 2003, Liani et al. 2004). When ubiquitinated by SIAH1, SNCAIP is targetted for proteasomal degradation (Nagano et al. 2003). SIAH1 and SIAH2 are inhibited by the 1A isoform of SNCAIP (Szargel et al. 2009). SIAH1 can bind the brain-enriched E2 ubiquitin-conjugating enzyme UBE2L6 (Lee et al. 2008) but the E2 involved in SNCAIP ubiquitination has not been established.

Synphilin-1 (SNCAIP) is a presynaptic protein that associates with synaptic vesicles (Ribeiro et al. 2002). It is present in many types of cytoplasmic inclusions, where it colocalizes with alpha-synuclein. It is associated with Parkinson's Disease (PD) because it is an intrinsic component of Lewy bodies (Wakabayashi et al. 2000) and a mutation of the SNCAIP gene has been identified in some PD patients (Marx et al. 2003), suggesting that accumulation of synphilin-1 and its interaction with alpha-synuclein may be relevant for Lewy body formation in PD.

Synphilin-1 (SNCAIP) is ubiquitinated by several other E3 ubiquitin-ligases, including Parkin (Chung et al. 2001) and Dorfin (Ito et al. 2003).
R-HSA-5667111 (Reactome) SNCAIP is ubiquitinated by several different E3 ubiquitin-ligases, including Parkin (PARK2). PARK2 overexpression with SNCAIP in cell culture leads to the formation of protein aggregates (Chung et al. 2001). PARK2 preferentially mediates the addition of lysine-63 (K63)-linked polyubiquitination of SNCAIP (Lim et al. 2005). This leads to SNCAIP degradation only at an unusually high PARK2 to SNCAIP ratio (Lim et al. 2005). K63-linked ubiquitination may be a signal that leads to the degradation of inclusions by autophagy when the ubiquitin-proteasome system is dysfunctional (Lim et al. 2005, Tan et al. 2008).
R-HSA-5692495 (Reactome) Beta-secretase 1 (BACE1) catalyses the rate-limiting step of the cleavage of amyloid precursor protein (APP(18-770)), resulting in the generation of the beta-amyloid proteins 42 and 40 (APP(672-713) and APP(673-711) respectively). These peptides are thought to be the main fibril-forming peptides (Qui et al. 2015).
R-HSA-5692934 (Reactome) Beta-secretase 1 (BACE1, memapsin-2) mediates the proteolytic processing of amyloid precursor protein (APP). BACE1 is transported from the plasma membrane to endosomes where APP hydrolysis takes place. The acid-cluster-dileucine (ACDL) motif in the cytosolic domain of BACE1 is able to bind to the VHS domain of ADP-ribosylation factor-binding proteins 1, 2 and 3 (GGA1,2,3) which play a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. This is the presumed recognition step for BACE1 transport to endosomes (He et al. 2003).
R-HSA-5692941 (Reactome) Beta-secretase 1 (BACE1, memapsin-2) mediates the proteolytic processing of amyloid precursor protein (APP). BACE1 is transported from the cell surface to endosomes where APP hydrolysis takes place. The acid-cluster-dileucine (ACDL) motif in the cytosolic domain of BACE1 is able to bind to the VHS domain of ADP-ribosylation factor-binding proteins 1, 2 and 3 (GGA1,2,3) which play a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. This is the presumed recognition step for BACE1 transport to endosomes (He et al. 2003).
R-HSA-5693001 (Reactome) N-acetyltransferase 8 and 8B (NAT8, 8B) can mediate the molecular stabilisation of BACE1, the membrane protein that acts as the rate-limiting enzyme in the generation of the Alzheimer disease amyloid beta-peptide. Specifically, nascent BACE1 is transiently acetylated on seven lysine residues in the ER lumen which protects the nascent protein from degradation in the ER Golgi intermediate compartment (ERGIC) and allows it to reach the Golgi apparatus (Ko & Puglielli 2009, Costantini et al. 2007). Lysine-acetylated BACE1 (7K-BACE1) is deacetylated in the Golgi apparatus.
R-HSA-5693071 (Reactome) Beta secretase 1 (BACE1) is acetylated on 7 lysine residues inthe ER lumen (7K-BACE1). This protects the nascent protein from degradation in the ER Golgi intermediate compartment (ERGIC) and allows it to reach the Golgi apparatus (Kandalepas & Vassar 2014). The mechanism of this translocation is unknown.
R-HSA-5693081 (Reactome) FURIN is the most likely endopeptidase that cleaves the BACE propeptide domain (BACE1(22-45)) to form the mature enzyme (7K-BACE1(46-501). Although the pro-enzyme possesses proteolytic activity, this activity is approximately doubled following removal of the prodomain (Bennett et al. 2000).
R-HSA-5693086 (Reactome) BACE1(46-501) translocates from the Golgi lumen to the plasma membrane (Walter et al. 2001).
R-HSA-5693092 (Reactome) Mature beta secretase 1, acetylated on 7 lysine residues (7K-BACE1(46-501), is deacetylated by an unknown deacetylase in the Golgi apparatus (Kandalepas & Vassar 2014).
R-HSA-6783332 (Reactome) The beta-amyloid proteins 42 and 40 (APP(672-713) and APP(673-711) respectively) are thought to be the main fibril-forming peptides implicated in neurodegenerative disorders. They translocate from the endosomal lumen to the extracellular region by an unknown mechanism (Qui et al. 2015).
R-HSA-976723 (Reactome) Serum amyloid P component (SAP) is a member of the pentraxin family, characterized by the formation of pentameric ring structures. Each member of the ring has two associated calcium ions. SAP is an acute phase reactant, highly induced by IL-6. It has 50% homology with the related C-reactive peptide.
R-HSA-976734 (Reactome) In addition to the main fibril peptide, mature amyloid fibrils have additional components. Serum amyloid P component (SAP) binds to all types of amyloid fibrils and is a universal constituent of amyloid deposits. SAP binding protects amyloid fibrils from proteolytic degradation (Tennent et al. 1995, Westermark 2005). SAP may function as a chaperone for amyloid formation (Coker et al. 2000).

Glycosaminoglycans (GAGs) and proteoglycans are found associated with all types of amyloid deposits (Alexandrescu 2005). Of the different types of GAG heparan sulfate and dermatan sulfate are the most prominent in amyloid deposits (Hirschfield & Hawkins, 2003). GAGs have been implicated in the nucleation of fibrils, they can also stabilize mature fibrils against dissociation (Yamaguchi et al. 2003) and proteolytic degradation (Gupta-Bansal et al. 1995).

Perlecan coimmunolocalizes with all types of amyloids (Snow & Wright 1989), accelerating fibril formation (Castillo et al. 1998), stabilizing them once formed (Castillo et al. 1997), and protecting them from proteolytic degradation (Gupta-Bansal et al. 1995).

ApoE tightly binds to soluble ABeta peptide forming complexes that resist dissociation; it also binds to ABeta in its fibril form (Bales et al. 2002).
R-HSA-976817 (Reactome) At physiological pH serum amyloid P component is a decamer of two pentameric rings lying face to face. This non-covalent interaction is readily dissociated by reducing the pH.
R-HSA-977136 (Reactome) Amyloid fibril formation is associated with a wide range of diseases (Chiti & Dobson 2006), though the accumulation and deposition of fibrillar material does not correlate well with disease pathogenesis and it is now widely believed that oligomeric amyloid forms are largely responsible for the cytotoxic effects of amyloid (Glabe 2009). Fibrils have been described as more like crystalline polymer structures than the protein monomers they are derived from (Wetzel et al. 2007). In vitro, fibril formation is usually preceded by the association of monomers into oligomeric structures (Kodali & Wetzel 2007), though this remains to be established in vivo. Amyloid-beta forms spherical structures with around 12 units (Bernstein et al. 2005). Larger structures called protofibrils are also observed, non-spherical filamentous structures lacking a periodic substructure (Goldsbury 2005).
R-HSA-977224 (Reactome) Serum amyloid P component (SAP) binds DNA and chromatin in a calcium dependent manner in physiological conditions (Pepys et al. 1987). This binding displaces H1-type histones (Butler et al. 1990), solubilizing chromatin which is otherwise insoluble in extracellular fluids. SAP may therefore participate in the in vivo handling of chromatin exposed by cell death. SAP knockout mice spontaneously develop antinuclear autoimmunity and severe glomerulonephritis, a phenotype resembling human systemic lupus erythematosus, a serious autoimmune disease, suggesting that SAP binding may play a role in reducing the immunogenicity of chromatin and preventing autoimmunity (Bickerstaff et al. 1999).
SIAH1, SIAH2:SNCAIPArrowR-HSA-5658092 (Reactome)
SIAH1, SIAH2:SNCAIPmim-catalysisR-HSA-5667107 (Reactome)
SIAH1, SIAH2R-HSA-5658092 (Reactome)
SIAH1,SIAH2:UBE2L6:Ubiquitin:SNCAArrowR-HSA-5658496 (Reactome)
SIAH1,SIAH2:UBE2L6:Ubiquitin:SNCAR-HSA-5660753 (Reactome)
SIAH1,SIAH2:UBE2L6:Ubiquitin:SNCAmim-catalysisR-HSA-5660753 (Reactome)
SIAH1,SIAH2:UBE2L6:UbiquitinR-HSA-5658496 (Reactome)
SIAH1:UBE2L6:Ub-SNCAArrowR-HSA-5660753 (Reactome)
SIAH1:UBE2L6:Ub-SNCAR-HSA-5660757 (Reactome)
SIAH1ArrowR-HSA-5660757 (Reactome)
SNCAArrowR-HSA-5661161 (Reactome)
SNCAIP-1ATBarR-HSA-5667107 (Reactome)
SNCAIP:SNCAsArrowR-HSA-5658104 (Reactome)
SNCAIPR-HSA-5658092 (Reactome)
SNCAIPR-HSA-5658104 (Reactome)
SNCAIPR-HSA-5658574 (Reactome)
SNCAIPR-HSA-5667107 (Reactome)
SNCAIPR-HSA-5667111 (Reactome)
SNCAR-HSA-5658496 (Reactome)
SNCAsR-HSA-5658104 (Reactome)
Serum

amyloid P-component

pentamer:Double-stranded DNA		ArrowR-HSA-977224 (Reactome)
Serum amyloid

P-component

homopentamer		ArrowR-HSA-976723 (Reactome)
Serum amyloid

P-component

homopentamer		R-HSA-976734 (Reactome)
Serum amyloid

P-component

homopentamer		R-HSA-976817 (Reactome)
Serum amyloid

P-component

homopentamer		R-HSA-977224 (Reactome)
Serum amyloid P decamerArrowR-HSA-976817 (Reactome)
UBE2L6ArrowR-HSA-5660757 (Reactome)
USP9X:Ub-SNCAArrowR-HSA-5661157 (Reactome)
USP9X:Ub-SNCAR-HSA-5660752 (Reactome)
USP9X:Ub-SNCAmim-catalysisR-HSA-5660752 (Reactome)
USP9XArrowR-HSA-5661161 (Reactome)
USP9XR-HSA-5661157 (Reactome)
USPX9:SNCAArrowR-HSA-5660752 (Reactome)
USPX9:SNCAR-HSA-5661161 (Reactome)
Ub-SNCAArrowR-HSA-5660757 (Reactome)
Ub-SNCAR-HSA-5661157 (Reactome)
UbiquitinArrowR-HSA-5660752 (Reactome)
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