Membraneless organelles
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What occurs in the nucleolus?
Ribosome biogenesis
What occurs in paraspeckles?
Regulation of gene expression
What occurs in nuclear speckles?
Storage of splicing factors
What occurs in cajal bodies
Regulation of snRNP maturation
What occurs in PML bodies
Regulation of transcription and protein storage
What do membraneless organelles behave like?
Liquid drops
What do membranelles organelles form by?
Liquid liquid phase seperation
What are scaffold and clients
Key set of proteins and RNA that drive membraneless organelle formation
Regulation of LLPS
Proteins that drive are LLPS are multivalent and have intrisically disordered regions (IDRs)
Does Liquid to solid phase transitions associate with disease?
Yes
What do stress granules contain?
• mRNAs stalled in translation initiation (pre-initiation complexes) • Various translation initiation factors • RNA-binding proteins, and many non-RNA-binding proteins
Assembly of stress granules
mRNA associates with 40S to from PIC 60S seperates, leading to accumulation of 40S-mRNA complexes Puromycin promotes SGs, disrupts translating ribosome
Formation of PICs and mRNA translation under basal conditions
eIF4F complex recognises 5’ cap eIF2 binds initiator tRNA this complex combines with eIF3-40S to form 43S PIC 60S ribosomal particle binds 43S PIC associates with eIF4F-mRNA to form 48S-PIC
Inhibition of translation initiation promotes SG formation
mTOR inhibition reduced phosphorylation of 4E-BP, now can bind eIF4E displacing it from complex with mrNA Phosphorylation of EIF2 prevents binding to tRNAi Drugs can interfere with eIF4F complex displacing it from mRNA Incomplete PICs bind RBPs that nucleate SGs
What is a key player in pathology of neurodegenerative diseases
TDP-43
What is the structure if TDP-43
Folded N terminal domain, NLS, NES and 2 RNA recognition motifs and unstructured C-terminal tail
What processing of TDP-43 cause disease?
Phosphorylation
What of protein assembly is associated with disease?
Protein assemb,y into amyloids
What does TDP-43 form?
Amyloid fibrils
What are amyloids?
Solid aggregates of beta-sheet rich fibrils
What virus is a model system of viral factories
Rotavirus, major cause of acute gastroenteritis in infants and young kids
What is a chemical probe to differentiation between liquid-like and gel-like states of membraneless organelles?
1,6-hexanediol
Early infection viral factories are completely dissolved by what?
1,6-hexanediol
RSV replication is blocked by what>
Small molecules which reduce fluidity of viral factories and decreases viral replication