Biological roles of prion domains

Abstract

In vivo amyloid formation is a widespread phenomenon in eukaryotes. Self-perpetuating amyloids provide a basis for the infectious or heritable protein isoforms (prions). At least for some proteins, amyloid-forming potential is conserved in evolution despite divergence of the amino acid (aa) sequences. In some cases, prion formation certainly represents a pathological process leading to a disease. However, there are several scenarios in which prions and other amyloids or amyloid-like aggregates are either shown or suspected to perform positive biological functions. Proven examples include self/nonself recognition, stress defense and scaffolding of other (functional) polymers. The role of prion-like phenomena in memory has been hypothesized. As an additional mechanism of heritable change, prion formation may in principle contribute to heritable variability at the population level. Moreover, it is possible that amyloid-based prions represent by-products of the transient feedback regulatory circuits, as normal cellular function of at least some prion proteins is decreased in the prion state.

Figure 1

Structural organization of prion proteins. QN: the QN-rich stretch. OR: the region of oligopeptide repeats. PrD-prion domain. Numbers correspond to amino acid (aa) positions. Arrows indicate domain and subdomain boundaries. N, M and C-N-proximal, middle and C-proximal regions of Sup35, respectively. The N/M and M/C boundaries are arbitrarily assigned to the second (aa 124) and third (aa 254) methionine residues of the Sup35 protein. See text for details.

Figure 2

Evolutionary comparison of the N-terminal domains of Sup35 homologs. Sequences are from www.ncbi.nlm.nih.gov. Taxonomical relationships are from www.ncbi. nlm.nih.gov/Taxonomy. Scales do not correspond to evolutionary distances. For QN and OR designations, see Fig. 1. Numbers on the right correspond to the size of the N-terminal region (in aa) in each case. Sequence data were obtained from www.ncbi.nlm.nih.gov. ? -refers to the cases where search for prion activity in S. cerevisiae has been performed but have not yielded positive results (O. Zemlyanko, A. Petrova and G. Zhouravleva, unpublished; K. Gokhale and Y. Chernoff, unpublished). NT, not tested.

Figure 3

Formation of the stress granules. Schematic structure of TIA protein. (Q) the Q-rich stretch. Other designations are as in Figure 1B Model showing formation of stress granules. Ribosome subunits are shown as ovals and TIA as black asterisk. See text for more details.

Figure 4

Role of amyloid in melanin polymerization. Glycoprotein Pmel17, that is a critical component of melanosome biogenesis, gives rise to two fragments, Mα and Mβ. Self-assembly of Mα leads to amyloid formation. Amyloid provides a scaffold for melanin polymerization.