Vitagliano, Proc. Natl Acad. Sci. USA 103:11533–11538, 2006; B, from S. Sambashivan et al., Nature 437:266–269, 2005; C, courtesy of David Eisenberg.)
Figure 3–33 The special protein aggregates that cause prion diseases.
(A) Schematic illustration of the type of conformational change in the PrP protein (prion protein) that produces material for an amyloid fibril. (B) The self-infectious nature of the protein aggregation that is central to prion diseases. PrP is highly unusual because the misfolded version of the protein, called PrP*, induces the normal PrP protein it contacts to change its conformation, as shown.
Amyloid fibrils were initially studied because they cause disease. But the same type of structure is now known to be exploited by cells for useful purposes. Eukaryotic cells, for example, store many different peptide and protein hormones that they will secrete in specialized “secretory granules,” which package a high concentration of their cargo in dense cores with a regular structure (see Figure 13–65). We now know that these structured cores consist of amyloid fibrils, which in this case have a structure that causes them to dissolve to release soluble cargo after being secreted by exocytosis to the cell exterior (Figure 3–34A). Many bacteria use the amyloid structure in a very different way, secreting proteins that form long amyloid fibrils projecting from the cell exterior that help to bind bacterial neighbors into biofilms (Figure 3–34B). Because these biofilms help bacteria to survive in adverse environments (including in humans treated with antibiotics), new drugs that specifically disrupt the fibrous networks formed by bacterial amyloids have promise for treating human infections.
Until recently, those amyloids with useful functions were thought to be either confined to the interior of specialized vesicles or expressed on the exterior of cells, as in Figure 3–34. However, new experiments reveal that a large set of low complexity domains can form amyloid fibers that have functional roles in both the cell nucleus and the cell cytoplasm. These domains are normally unstructured and consist of stretches of amino acid sequence that can span hundreds of amino acids, while containing only a small subset of the 20 different amino acids. In contrast to the disease-associated amyloid in Figure 3–33, these newly discovered structures are held together by weaker noncovalent bonds and readily dissociate in response to signals—hence their name reversible amyloids.
Many proteins with such domains also contain a different set of domains that bind to specific other protein or RNA molecules. Thus, their controlled aggregation
Golgi amyloid template subunit cisterna fbril subunit of fbril (A) prion protein can adopt an abnormal, misfolded form normal Prp abnormal prion form protein of PrP protein (Prp*) (B) misfolded protein can induce formation of protein aggregates the conversion of more PrP to misfolded form creates a stable amyloid fbril protein aggregate in form of amyloid fbril
Figure 3–34 Two normal functions for amyloid fibrils. (A) In eukaryotic cells, protein cargo can be packed very densely in secretory vesicles and stored until signals cause a release of this cargo by exocytosis. For example, proteins and peptide hormones of the endocrine system, such as glucagon and calcitonin, are efficiently stored as short amyloid fibrils, which dissociate when they reach the cell exterior. (B) Bacteria produce amyloid fibrils on their surface by secreting the precursor proteins; these fibrils then create biofilms that link together, and help to protect, large numbers of individual bacteria.