Amyloid
Amyloids are aggregates of proteins characterised by a fibrillar morphology of typically 7–13 nm in diameter, a β-sheet secondary structure and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions and form fibrous deposits within and around cells. These protein misfolding and deposition processes disrupt the healthy function of tissues and organs.
Such amyloids have been associated with more than 50 human diseases, including amyloidosis, and may play a role in some neurodegenerative diseases. Some of these diseases are mainly sporadic and only a few cases are familial. Others are only familial. Some result from medical treatment. Prions are an infectious form of amyloids that can act as a template to convert other non-infectious forms. Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans.
Amyloids have been known to arise from many different proteins. These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.
An unusual secondary structure named α sheet has been proposed as the toxic constituent of amyloid precursor proteins, but this idea is not widely accepted at present.
Definition
The name amyloid comes from the early mistaken identification by Rudolf Virchow of the substance as starch, based on crude iodine-staining techniques. For a period, the scientific community debated whether or not amyloid deposits are fatty deposits or carbohydrate deposits until it was finally found that they are, in fact, deposits of albumin-like proteinaceous material.- The classical, histopathological definition of amyloid is an extracellular, proteinaceous fibrillar deposit exhibiting β-sheet secondary structure and identified by apple-green birefringence when stained with congo red under polarized light. These deposits often recruit various sugars and other components such as serum amyloid P component, resulting in complex, and sometimes inhomogeneous structures. 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 that polymerizes to form a cross-β structure, in vivo or in vitro, inside or outside cells. Microbiologists, biochemists, biophysicists, chemists and physicists have largely adopted this definition, leading to some conflict in the biological community over an issue of language.
Proteins forming amyloids in diseases
| Protein | Diseases | Official abbreviation |
| β amyloid peptide from Amyloid precursor protein | Alzheimer's disease, Hereditary cerebral haemorrhage with amyloidosis | Aβ |
| α-synuclein | Parkinson's disease, Parkinson's disease dementia, Dementia with Lewy bodies, Multiple system atrophy | AαSyn |
| PrPSc | Transmissible spongiform encephalopathy | APrP |
| Microtubule-associated protein tau | Various forms of tauopathies | ATau |
| Huntingtin exon 1 | Huntington's disease | HTTex1 |
| ABri peptide | Familial British dementia | ABri |
| ADan peptide | Familial Danish dementia | ADan |
| Fragments of immunoglobulin light chains | Light chain amyloidosis | AL |
| Fragments of immunoglobulin heavy chains | Heavy chain amyloidosis | AH |
| full length of N-terminal fragments of Serum amyloid A protein | AA amyloidosis | AA |
| Transthyretin | Senile systemic amyloidosis, Familial amyloid polyneuropathy, Familial amyloid cardiomyopathy, Leptomeningeal amyloidosis | ATTR |
| β-2 microglobulin | Dialysis related amyloidosis, Hereditary visceral amyloidosis | Aβ2M |
| N-terminal fragments of Apolipoprotein AI | ApoAI amyloidosis | AApoAI |
| C-terminally extended Apolipoprotein AII | ApoAII amyloidosis | AApoAII |
| N-terminal fragments of Apolipoprotein AIV | ApoAIV amyloidosis | AApoAIV |
| Apolipoprotein C-II | ApoCII amyloidosis | AApoCII |
| Apolipoprotein C-III | ApoCIII amyloidosis | AApoCIII |
| fragments of Gelsolin | Familial amyloidosis, Finnish type | AGel |
| Lysozyme | Hereditary non-neuropathic systemic amyloidosis | ALys |
| fragments of Fibrinogen α chain | Fibrinogen amyloidosis | AFib |
| N-terminally truncated Cystatin C | Hereditary cerebral hemorrhage with amyloidosis, Icelandic type | ACys |
| IAPP | Diabetes mellitus type 2, Insulinoma | AIAPP |
| Calcitonin | Medullary carcinoma of the thyroid | ACal |
| Atrial natriuretic factor | Cardiac arrhythmias, Isolated atrial amyloidosis | AANF |
| Prolactin | Pituitary prolactinoma | APro |
| Insulin | Injection-localized amyloidosis | AIns |
| Lactadherin / Medin | Aortic medial amyloidosis | AMed |
| Lactotransferrin / Lactoferrin | Gelatinous drop-like corneal dystrophy | ALac |
| Odontogenic ameloblast-associated protein | Calcifying epithelial odontogenic tumors | AOAAP |
| Pulmonary surfactant-associated protein C | Pulmonary alveolar proteinosis | ASPC |
| Leukocyte cell-derived chemotaxin-2 | Renal LECT2 amyloidosis | ALECT2 |
| Galectin-7 | Lichen amyloidosis, Macular amyloidosis | AGal7 |
| Corneodesmosin | Hypotrichosis simplex of the scalp | ACor |
| C-terminal fragments of TGFBI/Keratoepithelin | Lattice corneal dystrophy type I, Lattice corneal dystrophy type 3A, Lattice corneal dystrophy Avellino type | AKer |
| Semenogelin-1 | Seminal vesicle amyloidosis | ASem1 |
| Proteins S100A8/A9 | Prostate cancer | none |
| Enfuvirtide | Injection-localized amyloidosis | AEnf |
Non-disease and functional amyloids
Many examples of non-pathological amyloid with a well-defined physiological role have been identified in various organisms, including human. These may be termed as functional or physiological or native amyloid.- Functional amyloid in Homo sapiens:
- * Intralumenal domain of melanocyte protein PMEL
- * Peptide/protein hormones stored as amyloids within endocrine secretory granules
- * Receptor-interacting serine/threonine-protein kinase 1/3
- * Fragments of prostatic acid phosphatase and semenogelins
- Functional amyloid in other organisms:
- * Curli fibrils produced by E. coli, ''Salmonella, and a few other members of the Enterobacteriales. The genetic elements encoding the curli system are phylogenetic widespread and can be found in at least four bacterial phyla. This suggest that many more bacteria may express curli fibrils.
- * GvpA, forming the walls of particular Gas vesicles, i.e. the buoyancy organelles of aquatic archaea and eubacteria
- * Fap fibrils in various species of Pseudomonas
- * Chaplins from Streptomyces coelicolor
- * Spidroin from Trichonephila edulis
- * Hydrophobins from Neurospora crassa and other fungi
- * Fungal cell adhesion proteins forming cell surface amyloid regions with greatly increased binding strength
- * Environmental biofilms according to staining with amyloid specific dyes and antibodies.
- * Tubular sheaths encasing Methanosaeta thermophila filaments
- Functional amyloid acting as prions
- * Several yeast prions are based on an infectious amyloid, e.g. ; ; or ; and
- * Prion HET-s from Podospora anserina
- * Neuron-specific isoform of CPEB from Aplysia californica''
Structure
The term "cross-β" was based on the observation of two sets of diffraction lines, one longitudinal and one transverse, that form a characteristic "cross" pattern. There are two characteristic scattering diffraction signals produced at 4.7 and 10 Å, corresponding to the interstrand and stacking distances in β sheets. The "stacks" of β sheet are short and traverse the breadth of the amyloid fibril; the length of the amyloid fibril is built by aligned β-strands. The cross-β pattern is considered a diagnostic hallmark of amyloid structure.
Amyloid fibrils are generally composed of 1–8 protofilaments, each 2–7 nm in diameter, that interact laterally as flat ribbons that maintain the height of 2–7 nm and are up to 30 nm wide; more often protofilaments twist around each other to form the typically 7–13 nm wide fibrils. Each protofilament possesses the typical cross-β structure and may be formed by 1–6 β-sheets stacked on each other. Each individual protein molecule can contribute one to several β-strands in each protofilament and the strands can be arranged in antiparallel β-sheets, but more often in parallel β-sheets. Only a fraction of the polypeptide chain is in a β-strand conformation in the fibrils, the remainder forms structured or unstructured loops or tails.
For a long time our knowledge of the atomic-level structure of amyloid fibrils was limited by the fact that they are unsuitable for the most traditional methods for studying protein structures. Recent years have seen progress in experimental methods, including solid-state NMR spectroscopy and cryo-electron microscopy. Combined, these methods have provided 3D atomic structures of amyloid fibrils formed by amyloid β peptides, α-synuclein, tau, and the FUS protein, associated with various neurodegenerative diseases.
X-ray diffraction studies of microcrystals revealed atomistic details of core region of amyloid, although only for simplified peptides having a length remarkably shorter than that of peptides or proteins involved in disease. The crystallographic structures show that short stretches from amyloid-prone regions of amyloidogenic proteins run perpendicular to the filament axis, consistent with the "cross-β" feature of amyloid structure. They also reveal a number of characteristics of amyloid structures – neighboring β-sheets are tightly packed together via an interface devoid of water, with the opposing β-strands slightly offset from each other such that their side-chains interdigitate. This compact dehydrated interface created was termed a steric-zipper interface. There are eight theoretical classes of steric-zipper interfaces, dictated by the directionality of the β-sheets and symmetry between adjacent β-sheets. A limitation of X-ray crystallography for solving amyloid structure is represented by the need to form microcrystals, which can be achieved only with peptides shorter than those associated with disease.
Although bona fide amyloid structures always are based on intermolecular β-sheets, different types of "higher order" tertiary folds have been observed or proposed. The β-sheets may form a β-sandwich, or a β-solenoid which may be either β-helix or β-roll. Native-like amyloid fibrils in which native β-sheet containing proteins maintain their native-like structure in the fibrils have also been proposed. There are few developed ideas on how the complex backbone topologies of disulfide-constrained proteins, which are prone to form amyloid fibrils, adopt the amyloid β-sheet motif. The presence of multiple constraints significantly reduces the accessible conformational space, making computational simulations of amyloid structures more feasible.
One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations. This phenomenon is typically described as amyloid polymorphism.