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#nascent protein

2 public questions tagged with this topic.

Protein Sorting and Trafficking

Which domain of SRP binds to signal sequences on nascent proteins?

Specificity of signal recognition particle for hydrophobic targeting signals resides within C-terminal M domain of 54 kilodalton subunit SRP54. Structural analyses of bacterial homolog Ffh and mammalian SRP54 show M domain folds into deep groove lined almost exclusively with methionine side chains whose flexible thioether and long aliphatic chain create plastic hydrophobic bristle adaptable to varied signal sequence compositions and lengths. Basic residues surrounding groove interact with phosphate backbone of 7SL RNA and ribosomal proteins L23 and L29 near peptide exit tunnel. Adjacent NG GTPase domains dimerize with SRP receptor SRα via GTP-dependent interaction but do not contact signal directly. Upon signal accommodating as alpha-helix inside groove, conformational change extends to linker connecting M and NG domains, signaling Alu domain to pause translation. ATPase or BiP domains absent from SRP. This methionine-rich architecture explains how single particle binds hundreds of diverse ER targeting signals with high affinity yet promiscuous selectivity, ensuring efficient capture of secretory proteins early during synthesis preventing cytosolic mislocalization, aggregation and degradation by proteasome quality control and maintaining secretory flux.

Ref: Keenan et al., Annu Rev Biochem 70: 2001, SRP54 M Domain Binds Signal Sequences.

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Protein Sorting and Trafficking

The signal sequence of a nascent protein is cleaved by:

N-terminal signal peptides exhibit tripartite organization essential for targeting and cleavage: positively charged n-region with one to three basic residues, hydrophobic core h-region of seven to twelve aliphatic residues forming alpha-helix, and polar c-region containing signal peptidase recognition motif Ala-X-Ala at positions minus three and minus one relative to cleavage site, often followed by small residues. Once nascent chain enters ER lumen through Sec61 channel, signal peptidase complex anchored on lumenal face performs co-translational cleavage. Heteromeric complex includes two catalytic subunits SEC11A and SEC11C that are serine proteases of S26 family using Ser-His-Asp catalytic triad, plus accessory subunits SPCS1, SPCS2, SPCS3 stabilizing assembly and positioning active site near membrane interface. Catalytic serine attacks carbonyl after c-region, hydrolyzing bond and liberating mature protein from membrane-tethered signal. Cleaved signal peptides further degraded by intramembrane signal peptide peptidase. Sec61 itself lacks proteolytic activity, SRP receptor only delivers, translocon pore conducts, so efficient cleavage is prerequisite for subsequent folding, N-glycosylation and trafficking beyond ER, preventing retention as membrane-anchored precursor that could disrupt membrane integrity.

Ref: Paetzel et al., Chem Rev 102: 2002, Signal Peptidase Cleaving Signal Sequences.

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