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#nascent proteins

2 public questions tagged with this topic.

Protein Sorting and Trafficking

The function of the SRP (Signal Recognition Particle) is to:

Signal recognition particle integrates targeting and translation control to ensure secretory proteins avoid premature cytosolic folding and aggregation. Particle consists of 7SL RNA scaffold folding into Alu and S domains and six proteins. Most critical subunit SRP54 contains N domain four-helix bundle, central GTPase domain and C-terminal M domain rich in methionines that forms deep groove accommodating diverse hydrophobic signal sequences through flexible sulfur-containing side chains providing plastic hydrophobic surface adaptable to many sequences. Binding occurs when signal emerges from ribosome, inducing structural rearrangement transmitted to Alu domain formed by SRP9/14 heterodimer and RNA hairpin that interacts with elongation factor binding site near GTPase center of ribosome, slowing elongation by competing with incoming aminoacyl-tRNA. This pause extends time window for diffusion to ER membrane where heterodimeric SRP receptor SRα-SRβ, both GTPases, captures complex via GTP-dependent dimerization of NG domains. GTP hydrolysis drives hand-off of ribosome-nascent chain to Sec61 and recycles SRP. COPII transport, BiP ATPase activation and vesicle docking are unrelated to primary SRP activity of recognition and pausing, ensuring fidelity and targeting efficiency.

Ref: Egea et al., Curr Opin Struct Biol 15: 2005, SRP Function in Signal Recognition and Pause.

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Protein Sorting and Trafficking

Which of the following recognizes the signal sequence of nascent proteins targeting the ER?

Early sorting of nascent secretory and membrane proteins is performed by signal recognition particle, conserved ribonucleoprotein containing 7SL RNA scaffold and six protein subunits. When hydrophobic signal sequence of about eight to twelve non-polar residues emerges from ribosomal exit tunnel, methionine-rich M domain of SRP54 forms flexible hydrophobic groove whose abundance of sulfur-containing methionine side chains allows plastic accommodation of diverse signal sequences via induced fit. Binding is communicated through 7SL RNA to Alu domain comprised of SRP9 and SRP14 heterodimer that docks at elongation factor binding site, temporarily pausing translation to prevent premature folding and aggregation in cytosol. SRP-ribosome-nascent chain complex then diffuses to ER where GTP-dependent interaction with heterodimeric SRP receptor made of SRα and SRβ GTPases delivers complex to Sec61 channel for hand-off. Ran-GTP controls nuclear import via importins, KDEL receptor retrieves escaped ER chaperones via COPI, Rab GTPases govern vesicle tethering and fusion specificity, none directly scan ribosome exit tunnel for hydrophobic nascent signals at this early checkpoint of protein sorting to ER lumen.

Ref: Lodish et al., Molecular Cell Biology, 9th ed., Chapter 13: SRP Recognizes Signal Sequences.

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