Amyloid fiber formation (Homo sapiens)
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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.
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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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.
amyloid P-component
pentamer:Double-stranded DNAP-component
homopentamerFibrils 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.
Annotated Interactions
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).
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).
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).
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).
The trafficking of ADAM10 is regulated by a subgroup of the tetraspanin superfamily referred to as TspanC8 tetraspanins. TSPAN4, 14, 15 and 33 are thought to mediate ADAM10 exit from the ER and transport to the plasma membrane in a variety of ways (Noy et al. 2016, Jouannet et al. 2016).
The trafficking of ADAM10 is regulated by a subgroup of the tetraspanin superfamily which have eight cysteines in the largest of the two extracellular domains and are referred to as TspanC8 tetraspanins. Tetraspanins associate specifically and directly with a limited number of proteins, and also with other tetraspanins, thereby generating a "tetraspanin web". Through these interactions, tetraspanins are believed to have a role in cell and membrane compartmentalisation (Charrin et al. 2014). TSPAN4, 14, 15 and 33 are thought to mediate ADAM10 exit from the ER and transport to the plasma membrane in a variety of ways (Noy et al. 2016, Jouannet et al. 2016).
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).amyloid P-component
pentamer:Double-stranded DNAP-component
homopentamerP-component
homopentamerP-component
homopentamerP-component
homopentamer