Amyloid formation involves a lag phase (also called nucleation phase), an exponential phase (also called growth phase) and a plateau phase (also called saturation phase), as shown in the figure. Indeed, when the quantity of fibrils is plotted versus time, a sigmoidal time course is observed reflecting the three distinct phases. In the simplest model of nucleated polymerization (marked by red arrows in the figure below), individual unfolded or partially unfolded polypeptide chains (monomers) convert into a nucleus (monomer or oligomer) via a thermodynamically unfavourable process that occurs early in the lag phase. Fibrils grow subsequently from these nuclei through the addition of monomers in the exponential phase.A different model, called nucleated conformational conversion and marked by blue arrows in the figure below, was introduced later on to fit some experimental observations: monomers have often been found to convert rapidly into misfolded and highly disorganized oligomers distinct from nuclei. Only later on, will these aggregates reorganise structurally into nuclei, on which other disorganised oligomers will add and reorganise through a templating or induced-fit mechanism (this nucleated conformational conversion model), eventually forming fibrils.Normally folded proteins have to unfold partially before aggregation can take place through one of these mechanisms. In some cases, however, folded proteins can aggregate without crossing the major energy barrier for unfolding, by populating native-like conformations as a consequence of thermal fluctuations, ligand release or local unfolding occurring in particular circumstances.
Proteins forming amyloids in diseases
To date, 37 human proteins have been found to form amyloid in pathology and be associated with well-defined diseases. The International Society of Amyloidosis classifies amyloid fibrils and their associated diseases based upon associated proteins (for example ATTR is the group of diseases and associated fibrils formed by TTR). A table is included below. 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 (RIP1/RIP3)
Fragments of prostatic acid phosphatase and semenogelinsFunctional amyloid in other organisms:
Curli fibrils produced by E. coli, Salmonella, and a few other members of the Enterobacteriales (Csg). The genetic elements (operons) 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 (spider) (Spider silk)
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 filamentsFunctional amyloid acting as prions
Several yeast prions are based on an infectious amyloid, e.g.