Prions, amyloids, and RNA: Pieces of a puzzle

Figures & data

FIGURE 1. RNA-modulating prions and amyloids, and cellular processes in which they are implicated. Shown are cellular processes or protein complexes, which are associated with corresponding prions and amyloids. Arrows connect consequent stages of the mRNA life cycle.

TABLE 1. RNA-modulating prions, amyloids, and amyloidogenic proteins

Gene / Protein	Amyloid (Prion)^*	Functions of the protein^**	Effects of prion or amyloid state	Organism	Compositionally biased regions^***
URE2 / Ure2	[URE3]	Transcriptional regulator of the nitrogen catabolism	Blocks interaction of Ure2 with Gln3^80 that causes preference of poor nitrogen sources	S. cerevisiae	N, Q/N
SWI1 / Swi1	[SWI^+]	Transcriptional regulator, subunit of SWI/SNF chromatin remodeling complex	Inhibits growth on the media with non-fermentable carbon sources,^40 provides resistance to benomyl^14	S. cerevisiae	A, N, Q, Q/N, T
SUP35 / Sup35	[PSI^+]	Translation release factor eRF3, mRNA decay	Reduces efficiency of translation termination^178	S. cerevisiae	E, G, K, Q, Q/N, Y
MOT3 / Mot3	[MOT3^+]	Transcription factor modulating mating, carbon metabolism, and stress response	Regulates flocculation; induction by ethanol and elimination by hypoxia^85	S. cerevisiae	A, H, N, P, Q, Q/N
CYC8 / Cyc8	[OCT^+]	Transcriptional repressor and activator, subunit of Cyc8-(Ssn6)-Tup1 complex	Inhibits growth of the strains bearing cyc1 deletion on the media with non-fermentable carbon source lactate^41	S. cerevisiae	A, E, P, Q/N, Q
SFP1 / Sfp1	[ISP^+]	Transcription regulator of genes encoding ribosomal proteins; regulates response to nutrients and stress	Antisuppression of nonsense mutations;^87 enhances resistance to cycloheximide and paromomycin^42	S. cerevisiae	A, D, H, N, Q, Q/N, T
PUB1 / Pub1	[PUB1]	Stress granule assembly, 3′UTR mRNA-binding	Unclear; aggregates co-localize with P-bodies / stress granules^45	S. cerevisiae	M, N, Q, Q/N
PUB1 and SUP35 / Pub1 and Sup35	[PUB1 / SUP35]	Stress granule assembly / Translation release factor eRF3	Formation of microtubule-associated cytoskeleton-associated complex carrying translational machinery and important for maintaining the integrity of the microtubular cytoskelton^45	S. cerevisiae	E, G, K, M, N, Q, Q/N, Y
TIA1 / TIA1	[TIA1]	Stress granule assembly, 3′UTR mRNA-binding	Amyloid-like fibrils involved in stress granule assembly^111	M. musculus	Q
NUP100 / Nup100	[NUP100^+]	Subunit of nuclear pore complex; nucleocytoplasmic transport	Unknown, phenotypic manifestation is absent^43	S. cerevisiae	G, N, Q, Q/N, S, T
TP53 / p53	p53, mutant	Transcriptional repressor	Amyloid-like oligomers and fibrils associated with carcinogenesis^104,105	H. sapiens	A, P
HTT / huntingtin	huntingtin, mutant	Transcriptional regulator	Pathological amyloid-like inclusions associated with Huntington's disease^91	H. sapiens	D, L, P, Q, Q/N, V
ATN / atrophin-1	atrophin-1, mutant	Transcriptional repressor	Pathological amyloid-like inclusions associated with dentatorubral pallidoluysian atrophy^94	H. sapiens	D, E, G, H, P, Q, Q/N, R, S
TNRC6A / TNRC6A	TNRC6A	RNA-binding, component of P-bodies, involved in the regulation of post-transcriptional gene silencing through the RNA interference	Fibrils in P-bodies, function is unclear^120	H. sapiens	G, K, N, P, Q, Q/N, S, T, W,
DDX6 / DDX6	DDX6	RNA helicase found in P-bodies and stress granules, involved in translation suppression and mRNA degradation	Fibrils in P-bodies, function is unclear^121	H. sapiens	Q
TDP43 / TDP43	TDP43, mutant	Transcriptional repressor, component of stress-granules	Pathological inclusions associated with frontotemporal dementia and amyotrophic lateral sclerosis^127-129	H. sapiens	G, N
FUS / FUS	FUS, mutant	RNA-binding, component of hnRNP-complex	Pathological inclusions associated with amyotrophic lateral sclerosis and polyglutamine diseases^131,132	H. sapiens	G, Q, R, S, Y
HNRNPA1 / hnRNPA1	hnRNPA1, mutant	RNA-binding, involved in the packaging of pre-mRNA into hnRNP particles, transport of poly-A mRNA from the nucleus to the cytoplasm	Pathological, multisystem proteinopathy-associated intracellular amyloid-like inclusions^136	H. sapiens	G
HNRNPA2B1 / hnRNPA2B1	hnRNPA2B1, mutant	RNA-binding, associated with pre-mRNAs in the nucleus	Pathological, multisystem proteinopathy-associated intracellular amyloid-like inclusions^136	H. sapiens	G, Y
CPEB / CPEB	CPEB	RNA-binding, binds U-rich sequence located in the 3′ untranslated regions of mRNAs, thus either promoting, or inhibiting translation	Functional amyloid involved in the control of long-term memory; induction by 5HT^24,159	A. californica	P, Q, Q/N, S
orb2 / Orb2A	Orb2A	see above (CPEB)	see above (CPEB); induction by dopamine, octopamine, or tyramine^161,169	D. melanogaster	G, H, M, Q, Q/N, S
CPEB3 / CPEB3	CPEB3	see above (CPEB)	see above (CPEB); induction by dopamine, glutamate, or glycine^59,162,163	M. musculus	A, P, Q, Q/N

* Column indicates the special designation of amyloid (or prion, in the case of yeast prions).

** Based on data from the NCBI Gene database (http://www.ncbi.nlm.nih.gov/gene/), Saccharomyces Genome Database (http://www.yeastgenome.org/), and cited studies.

*** Overrepresented amino acids are shown. CBRs were predicted by SARP algorithm,¹⁷⁹ and the probability thresholds were set to 10⁻⁶ for single residue CBRs and 10⁻¹² for multiple residues CBRs to reduce false positives. CBRs for multiple residue were predicted for the Q/N pair only.

TABLE 2. Functional categories^* overrepresented in the subset of Q/N-rich proteins^** in comparison with the entire proteome of S. cerevisiae

Function	Total number of proteins in category	Number of Q/N-rich proteins	The level of significance
GO:0004674 protein serine threonine kinase activity	128	29	0.05
GO:0004713 protein tyrosine kinase activity	8	4	0.028455
GO:0016251 general RNA polymerase II transcription factor activity	72	20	0.05
GO:0005515 protein binding	486	62	0.04775
GO:0003702 RNA polymerase II transcription factor activity	147	50	0.05
GO:0030276 clathrin binding	13	6	0.047577
GO:0016563 transcription activator activity	50	26	0.05
GO:0016564 transcription repressor activity	39	16	0.05
GO:0004672 protein kinase activity	134	30	0.05
GO:0003723 RNA binding	442	56	0.04131
GO:0046914 transition metal ion binding	398	62	0.05
GO:0019899 enzyme binding	38	9	0.026086
GO:0016773 phosphotransferase activity alcohol group as acceptor	196	34	0.05
GO:0016566 specific transcriptional repressor activity	21	7	0.0416
GO:0001071 nucleic acid binding transcription factor activity	137	50	0.05
GO:0019208 phosphatase regulator activity	26	10	0.05
GO:0019888 protein phosphatase regulator activity	26	10	0.05
GO:0016301 kinase activity	222	34	0.047667
GO:0003704 specific RNA polymerase II transcription factor activity	56	24	0.05
GO:0019789 SUMO ligase activity	5	3	0.013763
GO:0030234 enzyme regulator activity	256	41	0.05
GO:0035091 phosphoinositide binding	66	16	0.048875
GO:0004535 poly(A)-specific ribonuclease activity	5	3	0.013763
GO:0008289 lipid binding	95	23	0.05
GO:0030528 transcription regulator activity	279	88	0.05
GO:0043565 sequence-specific DNA binding	261	77	0.05
GO:0008143 poly(A) RNA binding	7	4	0.038469
GO:0008270 zinc ion binding	313	56	0.05
GO:0060589 nucleoside-triphosphatase regulator activity	131	20	0.006615
GO:0070717 poly-purine tract binding	7	4	0.038469
GO:0008601 protein phosphatase type 2A regulator activity	5	3	0.013763
GO:0003729 mRNA binding	52	22	0.05
GO:0003727 single-stranded RNA binding	15	7	0.0482
GO:0016455 RNA polymerase II transcription mediator activity	30	8	0.029088
GO:0003700 sequence-specific DNA binding transcription factor activity	137	50	0.05
GO:0005543 phospholipid binding	84	21	0.05

* Functional analysis of the subset was performed in the “Gene Ontology” Database (http://www.geneontology.org/); fractions of proteins were compared by “GoMiner” software.

** The selection of Q/N-rich proteins from the S. cerevisiae proteome was obtained using the SARP algorithm.¹⁷⁹ The probability thresholds were set to 10⁻⁶ for single residue CBRs and 10⁻¹² for multiple residue CBRs; CBRs were detected for the N and Q residues, as well as for the Q/N pair.

FIGURE 2. Q/N-rich subunits of protein complexes in S. cerevisiae and their interactions. Shown is the interactome of Q/N-rich subunits of protein complexes containing more than one Q/N-rich subunit. Lines indicate physical protein-protein interactions (according to data from “String” database, http://string-db.org/). Experimentally proven prion and amyloid-forming proteins are indicated by black circles, while other Q/N-rich proteins are indicated by gray circles. Light gray rectangles indicate corresponding protein complexes (including their names, as indicated).

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