What are amyloid proteins ?
The term amyloid originated from macroscopic observations conducted on cerebral material in 1854 by Rudolph Virchow. The tissue abnormalities showed by this brain sample revealed some properties similar to those of cellulose, therefore Virchow called them amyloid, from the Latin amylum and the Greek amylon.
Five years later, Friedreich and Kekule discovered that the supposed cellulosic nature of amyloid was actually wrong, by demonstrating the apparent absence of carbohydrates in amyloid aggregates. Instead, proteins were found in significant amount, leading to the desription of a new class of proteins, called amyloid proteins. In the following years, and during the 20th century, what was first thought to be a single group of proteins proved to contain numerous families of proteins. Those showed an important variety of functions, and were found in organisms ranging from yeast to mammals.
Primary observations of amyloid aggregates using light microscopy and histopathologic dyes showed an amorphous structure. However, in 1927, Divry and Florkin pointed out a positive birefringence of the long axis of unstained and Congo red-stained amyloid deposit. Over the years, congophilia with apple green birefringence became the first specific trait of amyloid.
In the late 50's, the use of electron microscopy allowed Cohen and Calkins to demonstrate the fibrillar structure of amyloid. Many experiments led after that proved this fibrillar morphology to exist in all kinds of human or animal amyloidotic tissues. The fibrillar state became then the second criterion defining amyloid.
Over the last forty years, significant progress have been made, due to the development of isolation and purification techniques. In particular, the structure of the amyloid proteins has been highly studied, as were their potential ways of aggregation. This led, in 1968 and 1969, to the definition of the third distinctive feature of amyloid, the cross-beta shape showed by x-ray diffraction in the aggregates.
Formation of insoluble fibers by soluble proteins undergoing conformationnal changes is very common : under in vitro denaturing conditions, most proteins will assemble themselves into aggregates in every way similar to amyloid fibrils. But this phenomenon occurs in vivo only for a small number of proteins, the amyloid ones.
Indeed, under very specific conditions (genetic mutations, environmental factors, ...), amyloid proteins undergo structural modifications, giving birth to new stable isoforms, called amyloidogenic isoforms. The following aggregation leads to pathological symptoms, amyloid proteins beeing involved in numerous diseases, known as amyloidosis. Some of those pathologies are among the most serious neurodegenerative ones, like Alzheimer's, Huntington's, Parkinson's or the transmissible encephalopathies.
However, some papers recently brought a new light on the consequences of amyloid formation : the amyloidogenic isoforms and the aggregates may sometimes have important biological functions. For instance, the Het-s protein found in Neurospora Crassa is well-known for its role in cytoplasmic incompatibility [Balguerie et al., 2003]. The function of some proteins found in humans might also relie on their fibrillogenic nature, like Pmel17, involved in melanin storage in melanosomes [Berson et al, 2003], or a neuronal member of the CPEB family wich regulates mRNA translation and could be involved in memory process [Si et al., 2003]. Even A-beta, involved in Alzheimer's disease, may not be as neurotoxic as it was thought to be, but instead may have a neuroprotective function [Savory et al., 2002].
Some amyloid proteins, termed prions, show a very unusual behavior : not only do they form amyloid deposits, but they also possess the ability to spread the aggregation phenomenon to other cells, or even to other organisms.
The prion concept was originally proposed in 1982 by Stanley Prusiner, to explain the peculiar transmission of the Creutzfeldt-Jakob disease. He showed the propagating agent was of proteinous nature, consisting of little aggregates of a modified isoform of PrP (Prion Protein), a normal component of the cell. Further work allowed him to define a prion as "a proteinaceous infectious particle that lacks nucleic acid", a definition also known as the "protein-only hypothesis".
The PrP protein is the only mammalian prion protein known to date, but other prions have been found in yeast or in fungus, where the prion phenomenon seems to be widespread. In these unicellular organisms, prionic isoforms do not always induce pathological phenotypes : they can also work as non-genetic inheritance elements. The prion statement about infectious particles might then evolve into a wider definition, that would include the ability to propagate phenotypical variability.
There are currently 33 amyloid protein families stored in AmyPDB. All of those families are listed below, including the number of sequences collected for each of them.
| Name | Description | Listed sequences |
| (Apo)-Serum amyloid A |  Serum amyloid A is an acute phase protein. It is expressed mainly in the liver. Though its role is not well understood, it is involved in cholesterol regulation, activation of secretory cholesterol phospholipases, and mediation of monocytes, granulocytes and T-cells. It also possess inhibitory effects on inflammation. Pathologies SAA is a precursor protein in inflammation-associated reactive amyloidosis (AA-type). Among the 3 human isoforms, only SAA1 and SAA2 have been identified in amyloid aggregates. |
74 |
| (Pro)-Calcitonin | Calcitonin is a 32 residues peptide hormone, produced by the thyroid gland in humans. It lowers plasma calcium and phosphate levels without augmenting calcium accretion. Pathologies In medullary thyroid cancer (MTC), calcitonin produced by tumorous cells forms amyloid deposits. |
37 |
| A-beta protein precursor | The APP (Amyloid Precursor Protein) comprises a large extracellular N-terminal domain, a short hydrophobic membrane-spanning domain, and a short C-terminal region. The 40-residue Abeta is a proteolytic product of this protein, encompassing the end of the N-terminal region and the transmembrane domain. Aberrant catabolism of APP seems to lead to the formation of Abeta. Pathologies This peptide is implicated in the pathogenesis of Alzheimer's disease and aged Down's Syndrome (which is promoted by the acquisition of an additional copy of chromosome 21). In Alzheimer's disease, the brain is characterised by extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and vascular and neuronal damage. The major peptide found within these deposits is Abeta. |
125 |
| A-S2C casein | |
0 |
| ABriPP/ADanPP | This highly insoluble peptide is a fragment of a putative type-II single-spanning transmembrane precursor. Pathologies The Familial British Dementia (FBD), also called familial cerebral amyloid angiopathy-British type, is due to a single base substitution at the stop codon of the BRI gene. This mutation generates a 27 aa protein, wich 34 carboxy-terminal amino acids form the ABri peptide found in amyloid aggregates of FBD. |
3 |
| Alpha Synuclein | It is a presynaptic protein, the function of wich is still not fully understood. It might be involved in the modulation of synaptic transmission, in the regulation of the localization of vesicles in synapses, and in neuronal plasticity. Pathologies Alpha synuclein is involved in several neurodegenerative pathologies, called synucleinopathies, such as Alzheimer's and Parkinson's diseases, or progressive autonomic failure and neurodegeneration with type 1 brain iron accumulation. A 35 residues fragment, called NAC, has been found in senile plaques and Lewy bodies typical of Alzheimer's and Parkinson's diseases, while two mutations (Ala35Pro and Ala 53Thr) lead to the accumulation of the entire protein in Lewy bodies. |
21 |
| Apolipoprotein A I | It plays a critical role in lipid metabolism : it is the major protein component of high density lipoprotein particles and plays a key role in the solubilization of lipids in these particles, the activation of lecithin cholesterol acyltransferase, the binding of high density lipoprotein to cell surfaces, and the promotion of cholesterol efflux from cells. Pathologies The N-terminal region of apolipoprotein A-1 has been found in amyloid fibrils of autosomal dominant systemic amyloidosis. Those amyloidosis are due to either the wild type apolipoprotein A1, or mutants of this protein, like Arg84 or Iowa variants. |
54 |
| Apolipoprotein A II | |
0 |
| Apolipoprotein A IV | |
0 |
| Atrial natriuretic factor | The atrial natriuretic factor plays an important role in the homeostasis of blood pressure as well as in sodium balance. Pathologies Aggregates containing the atrial natiurectic factor are characteristic of the Isolated Atrial Amyloid (IAA), a very common age-related amyloid form only seen in the atria of the heart. |
34 |
| Beta 2 Microglobulin | Beta 2 Microglobulin is the non-covalently bound light-chain of the class I human leukocyte antigen (HLA class 1). Pathologies Beeing normally degraded by kidneys, serum beta 2 microglobulin accumulates in case of renal failure, leading to the aggregation of the full length protein, mosttly in the musculoskeletal system. |
141 |
| Corneodesmin | |
0 |
| Cystatin C | Cystatin C, as well as other cystatins, is a natural cysteine protease inhibitor. Pathologies Wild type cystatin C has been shown to accumulate within amyloid-beta (A beta) amyloid deposits in Alzheimer's disease (AD) brain. Aggregation of calcitonin is also involved in sporadic cerebral amyloid angiopathy, while a variant human cystatin C (L68Q) is responsible for autosomal dominant cerebral amyloid angiopathy. |
67 |
| Fibrinogen alpha | Fibrinogen is an acute phase protein as well as a component of the coagulation cascade. It is found in hexameres of alpha, beta and gamma chains. Pathologies Arg554Leu and Glu526Val mutations are responsible for autosomal dominant hereditary hepatic or renal amyloidosis. |
59 |
| Galectin | |
0 |
| Gelsolin | This calcium-dependent actin-binding protein modulates actin filament length. It thus influences the structure of the cytoskeleton and plays a key role in cellular motility and differentiation. Pathologies Wild-type gelsolin is normally stabilized by Ca2+ binding. This stabilization lacks in D187N and D187Y variants, allowing access to a furin cleavage site. Furin processing liberates an amyloidogenic fragment, which aggregation leads to gelsolin familial amyloidosis. |
39 |
| Huntingtin | Huntingtin is involved in fast axonal trafficking. Pathologies Polyglutamine expansion in the N-terminal region of huntingtin plays a central role in Huntington's disease, by causing protein aggregation that leads to neurotoxicity. |
19 |
| Immunoglobulin heavy chain | |
0 |
| Immunoglobulin light chain | Immunoglobulins are large glycoproteins that are secreted by plasma cells. They are acting as antibodies in the immune response by binding with specific antigens. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM. Pathologies Light-chain (L-chain) amyloidosis is characterized by deposition of fibrillar aggregates composed of the N-terminal L-chain variable region (VL) domain of an immunoglobulin, generally in individuals overproducing a monoclonal L chain. |
0 |
| Insulin | This hormone is secreted by the islets of Langerhans, and is involved in the regulation of the metabolism of carbohydrates and fats, especially the conversion of glucose to glycogen, which lowers the blood glucose level. Pathologies Localised amyloidosis has been shown at the sites of injections for a patient with type 1 (insulin-dependent) diabete. Insulin aggregates have also been found in insulin infusion pump. |
160 |
| Islet amyloid polypeptide | IAPP is an hormone produced by pancreatic beta cells, that moderates the glucose lowering effects of insulin. Pathologies IAPP is the peptide subunit of amyloid found in pancreatic islets of type 2 diabetic patients and in insulinomas. |
17 |
| Kerato-epithelin | |
0 |
| Lactadherin | This glycoprotein was previously known to be expressed by mammary epithelial cells as a cell surface protein and secreted as part of the milk fat globule membrane. But recently, it was found to be expressed by aortic medial smooth muscle cells. A possible function has been shown in vitro : lactadherin might act as an anticoagulant, by competing with blood coagulation proteins for phospholipid binding sites. Pathologies The aggregation of a 50 residues fragment of lactadherin, called medin, leads to aortic medial amyloid, a form of localized amyloid very common in individuals older than 60 years. But the importance and effects of those amyloid deposits remain unknown. |
5 |
| Lactoferrin | Lactoferrin is a red iron-binding protein synthesized by neutrophils and glandular epithelial cells. It is found in many human secretions (as tears and milk), retarding bacterial and fungal growth. Pathologies Amyloid deposits containing lactoferrin have been discovered in the cornea, seminal vesicles, and brain. |
34 |
| Leukocyte chemotactic factor-2 | |
0 |
| Lung surfactant protein | This 35-residues protein is the major component of lung surfactant. Pathologies The conformation of SP-C can change from a monomeric alpha-helix to beta-sheet aggregates involved in the pulmonary alveolar proteinosis (PAP). |
16 |
| Lysozyme | It is an enzyme occurring naturally in egg white, human tears, saliva, and other body fluids, capable of degrading peptidoglycane and thereby acting as a mild antiseptic. Pathologies Mutations in the lysozyme gene can lead to the aggregation of the human protein, therefore to non-neuropathic systemic amyloidosis. |
122 |
| Odontogenic ameloblast-associated protein | |
0 |
| Prion Protein | Although the actual function of PrP remains unknown, many hypothesis are proposed, such as involvement in signal transmission or in copper regulation, as well as a possible function of copper-dependent superoxide dismutase. Pathologies PrP is the well-known prion protein of mammals. Its prionic form leads to many neurodegenerative diseases, including transmissible spongiform encephalopathies (scrapie in sheep, bovine spongiform encephalopathy in cattle or Creutzfeldt-Jacob disease and Gerstmann-Straussler-Scheinker syndrome in humans) and some dementias. |
353 |
| Prolactin | Prolactin is involved in a wide variety of biological processes, among wich are osmoregulation, development, reproduction, or immune regulation. Pathologies This hormone constitutes the amyloid fibrils of pituitary glands of aging individuals. |
112 |
| Semenogelin 1 | |
0 |
| Tau | Tau binds to and regulates the assembly and stability of neuronal microtubules. Pathologies Tau proteins are found in extracellular aggregates associated with Alzheimer's disease. Those proteins are also involved in many dementia, usually due to defects in the Tau gene. |
37 |
| Transthyretin | Transthyretin is a plasma protein that transports thyroxine. It can also form complexes with retinol binding proteins, so that those proteins are not lost by filtration in the kidney. Pathologies Single site mutations are associated with familial amyloid polyneuropathy (FAP). Those mutations destabilize tetrameric TTR, inducing monomeric amyloidogenic intermediates apparition. Those intermediates assembles into amyloid fibrils, whereas wild-type TTR remains tetrameric and nonamyloidogenic. |
54 |