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'''Amyloids''' are insoluble fibrous [[protein]] aggregations sharing specific structural traits. | '''Amyloids''' are insoluble fibrous [[protein]] aggregations sharing specific structural traits. | ||
==Definition | ==Definition Controversy== | ||
* The | * The name ''amyloid'' comes from the early mistaken identification of the substance [[starch|"starch"]] (''amylum'' in [[Latin]]), based on crude iodine-staining techniques. For a period, the [[Science|scientific]] community debated whether or not amyloid deposits were [[lipid|fatty]] deposits or [[carbohydrate]] deposits until it was finally resolved that it was neither, but rather a deposition of [[Protein|proteinaceous]] mass.<ref>Kyle, R.A. (2001) Amyloidosis: a convoluted story. ''Brit. J. Haem.'' 114:529-538. PMID 11552976</ref> | ||
* | * The classical, [[histopathology|histopathological]] definition of amyloid is an [[extracellular]], [[Protein|proteinaceous]] deposit exhibiting cross-beta structure. This is due to misfolding of unstable [[Protein|proteins]]. Common to most cross-beta type structures, they are generally identified by apple-green [[birefringence]] when stained with [[congo red|Congo Red]] and seen under [[polarization|polarized light]]. These deposits often recruit various [[Sugar|sugars]] and other components such as [[Serum Amyloid P component]], resulting in complex, and sometimes [[heterogeneous]] structures.<ref>Sipe, J. D. and Cohen, A.S. (2000) Review: History of the Amyloid Fibril. ''J. Struct. Biol.'' 130:88-98. PMID 10940217</ref> | ||
*Recently, this definition has come into question as some classic amyloid species have been observed in distinctly [[intracellular]] locations. | |||
* A more recent, ''biophysical'' definition is broader, including any [[polypeptide]] which adopts a cross-beta [[polymerization]], ''[[in vivo]]'', or ''[[in vitro]]''. Some of these, although demonstrably cross-beta sheet, fail other characteristic tests of amyloid, such as the [[Congo red|Congo Red]] [[Birefringence|birefringence test]]. [[Microbiologist|Microbiologists]] and [[Biophysics|biophysicists]] have largely adopted this definition, leading to some conflict in the [[Biology|biological]] community over the issue of language. | |||
==Diseases | ==Diseases Featuring Amyloids== | ||
*[[Amyloidosis]] | |||
*[[Medulary Carcinoma of the Thyroid]] | *[[Medulary Carcinoma of the Thyroid]] | ||
*[[Alzheimer's disease]] | *[[Alzheimer's disease]] | ||
*[[Transmissible spongiform encephalopathy]] | *[[Transmissible spongiform encephalopathy]] | ||
*Yeast Prions [Sup35] < | *Yeast Prions [Sup35] <ref>Nakayashiki, PNAS, 2005</ref> Rnq1 | ||
*Sporadic Inclusion Body Myositis (S-IBM) | *Sporadic Inclusion Body Myositis (S-IBM) | ||
==Non- | ==Non-Disease Amyloids== | ||
( | (Mostly using the biophysical definition) | ||
* Native amyloids in organisms | * Native amyloids in [[Organism|organisms]]: | ||
** Curli [[E. coli]] Protein (curlin) | ** Curli [[E. coli]] Protein (curlin) | ||
** Podospora Anserina Prion Het-s | ** Podospora Anserina Prion Het-s | ||
** [[Malaria]]l coat protein | **[[Malaria]]l coat protein | ||
** | ** Spider silk (not all spiders) | ||
** Mammalian [[melanosome]]s (pMel) | ** Mammalian [[melanosome]]s (pMel) | ||
** Tissue-type plasminogen activator (tPA) | **[[TPA|Tissue-type plasminogen activator (tPA)]] | ||
* Proteins and peptides known to make amyloid without any known disease | *[[Protein|Proteins]] and [[Peptide|peptides]] known to make amyloid without any known disease | ||
** [[Calcitonin]] | **[[Calcitonin]] | ||
* Proteins and peptides engineered to make amyloid | *[[Protein|Proteins]] and [[Peptide|peptides]] engineered to make amyloid | ||
==Amyloid Biophysics== | |||
* Amyloid is characterized by a cross-[[beta sheet]] [[quaternary structure]]; that is, the strands come from different [[Monomer|monomers]] and align [[perpendicular]] to the axis of the fibril. While amyloid is usually identified using [[fluorescent]] dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the [[Gold standard (test)|gold standard test]] to see if a structure contains cross-beta fibers is by placing a sample in an [[x-ray]] diffraction beam; there are two characteristic scattering diffraction signals produced at 4.7 and 10 [[Ångstrom]]s (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets. It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands. | |||
* Amyloid [[polymer]]ization is generally sequence-sensitive, that is, causing [[Mutation|mutations]] in the sequence can prevent self-assembly, especially if the [[mutation]] is a beta-sheet breaker, such as [[proline]]. For example, [[human]]s produce an amyloidogenic [[peptide]] associated with [[Diabetes mellitus type 2|type II diabetes]], but, in [[Rodent]]ia, a [[proline]] is substituted in a critical location and amyloidogenesis does not occur. | |||
Amyloid is | |||
* There are two broad classes of amyloid-forming [[polypeptide]] sequences. '''[[Glutamine|Glutamine-rich]]''' [[polypeptides]] are important in the amyloidogenesis of [[yeast]] and mammalian [[prions]], as well as [[Huntington's disease]]. When [[Peptide|peptides]] are in a beta-sheet conformation, particularly when the residues are parallel and in-register (causing alignment), [[Glutamine|glutamines]] can brace the structure by forming intrastrand [[Hydrogen bond|hydrogen bonding]] between its amide carbonyls and [[Nitrogen|nitrogens]]. In general, for this class of [[Disease|diseases]], [[toxicity]] correlates with [[glutamine]] content. This has been observed in studies of onset age for [[Huntington's disease]] (the longer the [[polyglutamine]] sequence, the sooner the [[Symptom|symptoms]] appear), and has been confirmed in a ''[[C. elegans]]'' model system with engineered [[polyglutamine]] [[Peptide|peptides]]. | |||
* Other [[polypeptides]] and [[Protein|proteins]], such as [[amylin]] and the [[Alzheimer's disease|Alzheimer's]] beta [[protein]] do not have a simple consensus sequence and are thought to operate by [[Hydrophobe|hydrophobic]] association. Among the [[hydrophobic]] residues, aromatic [[amino acids]] are found to have the highest amyloidogenic propensity. | |||
* For these [[Peptide|peptides]], cross-[[polymerization]] (fibrils of one [[polypeptide]] sequence causing other fibrils of another sequence to form) is a phenomenon observed [[in vitro]]. This phenomenon is important since it would explain interspecies [[prion]] propagation and amyloid biophysics differential rates of propagation, as well as a statistical link between [[Alzheimer's disease|Alzheimer's]] and [[diabetes]]. In general, cross-[[polymerization]] is more efficient the more similar the [[peptide]] sequence, though entirely dissimilar sequences can cross-[[Polymerization|polymerize]] and highly similar sequences can even be "blockers" which prevent [[polymerization]]. [[Polypeptides]] will not cross-[[Polymerization|polymerize]] their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events. | |||
* Xu, using [[Atomic force microscope|atomic force microscopy]], has shown in both [[lysozyme]] and human tau40, the formation of amyloid fibers is a two-step process in which [[Protein|proteins]] first aggregate into uniform colloidal spheres of ~20nm [[diameter]]. The spheres then join to form characteristic linear chains, which evolve over time into mature amyloid fibers. He proposes that aggregation drives conformational change and that a conformational change is not essential to initiate the aggregation process.<ref name="Xu">Xu S. Aggregation drives "misfolding" in protein amyloid fiber formation. ''Amyloid'' 2007 Jun;14(2):119-31. PMID 17577685</ref> | |||
==Amyloid Pathology== | |||
* The reasons for amyloid association with [[disease]] is unclear. In many cases, the deposits physically disrupt [[Tissue (biology)|tissue]] architecture, suggesting disruption of function by some bulk process. | |||
* In other cases, [[cell death]] is believed to precede amyloid deposition, suggesting that small amyloid-like [[Oligomer|oligomers]] (possibly but not necessarily biophysically amyloid) cause [[cell death]]. There is significant speculation that amyloid fibrils can also puncture [[Cell (biology)|cells]] or cause problems such as [[Ion|ionic]] imbalance in [[Cell (biology)|cells]]. | |||
* Further speculation has led to the [[hypothesis]] that while amyloid association may be the cause of health issues, the association itself is initiated by an underlying problem, such as one/some of the above mentioned side effects like [[calcium ion]] concentration imbalances. | |||
* For more information on the deposition of amyloid protein in the [[Human body|body]] [[Amyloidosis|(amyloidosis)]], click '''[[Amyloidosis|here]]'''. | |||
==Histological Staining== | |||
* Amyloid is typically identified by a change in the [[fluorescence]] intensity of planar [[aromatic]] [[dye]]s such as [[Thioflavin T]] or [[Congo red|Congo Red]]. [[Congo red|Congo Red]] postitivity remains the [[Gold standard (test)|gold standard]] for [[diagnosis]] of [[amyloidosis]]. | |||
Amyloid is typically identified by a change in the [[fluorescence]] intensity of planar [[aromatic]] [[dye]]s such as [[Thioflavin T]] or [[Congo red|Congo Red]]. | * This is generally attributed to the environmental change, as these dyes intercalate between beta-strands. | ||
* Congophillic amyloid plaques generally cause apple-green [[birefringence]], when viewed through crossed polarimetric filters. | |||
* To avoid nonspecific [[staining]], [[histology]] stains, such as [[haematoxylin]] and [[eosin]] [[stain]], are used to quench the dyes' activity in other places where the dye might bind, such as the [[Cell nucleus|nucleus]]. The dawn of [[antibody]] technology and [[immunohistochemistry]] has made specific [[staining]] easier, but this can often cause trouble because [[Epitope|epitopes]] can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the [[antibody]] recognizes. | |||
== See also == | == See also == | ||
Latest revision as of 23:46, 25 October 2019
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Amyloids are insoluble fibrous protein aggregations sharing specific structural traits.
Definition Controversy
- The name amyloid comes from the early mistaken identification of the substance "starch" (amylum in Latin), based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits were fatty deposits or carbohydrate deposits until it was finally resolved that it was neither, but rather a deposition of proteinaceous mass.[1]
- The classical, histopathological definition of amyloid is an extracellular, proteinaceous deposit exhibiting cross-beta structure. This is due to misfolding of unstable proteins. Common to most cross-beta type structures, they are generally identified by apple-green birefringence when stained with Congo Red and seen under polarized light. These deposits often recruit various sugars and other components such as Serum Amyloid P component, resulting in complex, and sometimes heterogeneous structures.[2]
- Recently, this definition has come into question as some classic amyloid species have been observed in distinctly intracellular locations.
- A more recent, biophysical definition is broader, including any polypeptide which adopts a cross-beta polymerization, in vivo, or in vitro. Some of these, although demonstrably cross-beta sheet, fail other characteristic tests of amyloid, such as the Congo Red birefringence test. Microbiologists and biophysicists have largely adopted this definition, leading to some conflict in the biological community over the issue of language.
Diseases Featuring Amyloids
- Amyloidosis
- Medulary Carcinoma of the Thyroid
- Alzheimer's disease
- Transmissible spongiform encephalopathy
- Yeast Prions [Sup35] [3] Rnq1
- Sporadic Inclusion Body Myositis (S-IBM)
Non-Disease Amyloids
(Mostly using the biophysical definition)
- Native amyloids in organisms:
- Curli E. coli Protein (curlin)
- Podospora Anserina Prion Het-s
- Malarial coat protein
- Spider silk (not all spiders)
- Mammalian melanosomes (pMel)
- Tissue-type plasminogen activator (tPA)
- Proteins and peptides known to make amyloid without any known disease
- Proteins and peptides engineered to make amyloid
Amyloid Biophysics
- Amyloid is characterized by a cross-beta sheet quaternary structure; that is, the strands come from different monomers and align perpendicular to the axis of the fibril. While amyloid is usually identified using fluorescent dyes, stain polarimetry, circular dichroism, or FTIR (all indirect measurements), the gold standard test to see if a structure contains cross-beta fibers is by placing a sample in an x-ray diffraction beam; there are two characteristic scattering diffraction signals produced at 4.7 and 10 Ångstroms (0.47 nm and 1.0 nm), corresponding to the interstrand and stacking distances in beta sheets. It should be noted that the "stacks" of beta sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned strands.
- Amyloid polymerization is generally sequence-sensitive, that is, causing mutations in the sequence can prevent self-assembly, especially if the mutation is a beta-sheet breaker, such as proline. For example, humans produce an amyloidogenic peptide associated with type II diabetes, but, in Rodentia, a proline is substituted in a critical location and amyloidogenesis does not occur.
- There are two broad classes of amyloid-forming polypeptide sequences. Glutamine-rich polypeptides are important in the amyloidogenesis of yeast and mammalian prions, as well as Huntington's disease. When peptides are in a beta-sheet conformation, particularly when the residues are parallel and in-register (causing alignment), glutamines can brace the structure by forming intrastrand hydrogen bonding between its amide carbonyls and nitrogens. In general, for this class of diseases, toxicity correlates with glutamine content. This has been observed in studies of onset age for Huntington's disease (the longer the polyglutamine sequence, the sooner the symptoms appear), and has been confirmed in a C. elegans model system with engineered polyglutamine peptides.
- Other polypeptides and proteins, such as amylin and the Alzheimer's beta protein do not have a simple consensus sequence and are thought to operate by hydrophobic association. Among the hydrophobic residues, aromatic amino acids are found to have the highest amyloidogenic propensity.
- For these peptides, cross-polymerization (fibrils of one polypeptide sequence causing other fibrils of another sequence to form) is a phenomenon observed in vitro. This phenomenon is important since it would explain interspecies prion propagation and amyloid biophysics differential rates of propagation, as well as a statistical link between Alzheimer's and diabetes. In general, cross-polymerization is more efficient the more similar the peptide sequence, though entirely dissimilar sequences can cross-polymerize and highly similar sequences can even be "blockers" which prevent polymerization. Polypeptides will not cross-polymerize their mirror-image counterparts, indicating that the phenomenon involves specific binding and recognition events.
- Xu, using atomic force microscopy, has shown in both lysozyme and human tau40, the formation of amyloid fibers is a two-step process in which proteins first aggregate into uniform colloidal spheres of ~20nm diameter. The spheres then join to form characteristic linear chains, which evolve over time into mature amyloid fibers. He proposes that aggregation drives conformational change and that a conformational change is not essential to initiate the aggregation process.[4]
Amyloid Pathology
- The reasons for amyloid association with disease is unclear. In many cases, the deposits physically disrupt tissue architecture, suggesting disruption of function by some bulk process.
- In other cases, cell death is believed to precede amyloid deposition, suggesting that small amyloid-like oligomers (possibly but not necessarily biophysically amyloid) cause cell death. There is significant speculation that amyloid fibrils can also puncture cells or cause problems such as ionic imbalance in cells.
- Further speculation has led to the hypothesis that while amyloid association may be the cause of health issues, the association itself is initiated by an underlying problem, such as one/some of the above mentioned side effects like calcium ion concentration imbalances.
- For more information on the deposition of amyloid protein in the body (amyloidosis), click here.
Histological Staining
- Amyloid is typically identified by a change in the fluorescence intensity of planar aromatic dyes such as Thioflavin T or Congo Red. Congo Red postitivity remains the gold standard for diagnosis of amyloidosis.
- This is generally attributed to the environmental change, as these dyes intercalate between beta-strands.
- Congophillic amyloid plaques generally cause apple-green birefringence, when viewed through crossed polarimetric filters.
- To avoid nonspecific staining, histology stains, such as haematoxylin and eosin stain, are used to quench the dyes' activity in other places where the dye might bind, such as the nucleus. The dawn of antibody technology and immunohistochemistry has made specific staining easier, but this can often cause trouble because epitopes can be concealed in the amyloid fold; an amyloid protein structure is generally a different conformation from that which the antibody recognizes.
See also
References
- ↑ Kyle, R.A. (2001) Amyloidosis: a convoluted story. Brit. J. Haem. 114:529-538. PMID 11552976
- ↑ Sipe, J. D. and Cohen, A.S. (2000) Review: History of the Amyloid Fibril. J. Struct. Biol. 130:88-98. PMID 10940217
- ↑ Nakayashiki, PNAS, 2005
- ↑ Xu S. Aggregation drives "misfolding" in protein amyloid fiber formation. Amyloid 2007 Jun;14(2):119-31. PMID 17577685
External links
- Amyloid Peptides at Bachem.com
- Amyloid Precursor Protein, CTF fragments at rpeptide.com
- Amyloid Treatment and Research Program at Boston University
- Amyloid: Journal of Protein Folding Disorders web page at tandf.co.uk
- Amyloidosis web page at Cornell University
- Information, support and advice to anyone with Amyloidosis, particularly in Australia (www.amyloidosisaustralia.org)
- Amyloidosis Support Network at amyloidosis.org
- UK National Amyloidosis Centre - one of the largest amyloid diagnosis and research centres at ucl.ac.uk
- Engineering Amyloid for material at University of California, Berkeley
- Amyloidosis Research Foundation amyloidosisresearchfoundation.org
- National Kidney and Urologic Diseases Information Clearinghouse at National Institute of Health
- Eubanks L, Rogers C, Beuscher A, Koob G, Olson A, Dickerson T, Janda K (2006). "A molecular link between the active component of marijuana and Alzheimer's disease pathology". Mol. Pharm. 3 (6): 773–7. PMID 17140265.