#signal sequence

Cell Organelles

The N-terminal signal sequence of secretory proteins is recognized by:

Targeting of secretory proteins to endoplasmic reticulum uses signal hypothesis where N-terminal fifteen to thirty amino acid hydrophobic sequence emerges from ribosome exit tunnel exposing binding site for signal recognition particle, a three hundred kDa ribonucleoprotein comprising seven SL RNA and six protein subunits including SRP54 that contains methionine-rich pocket accommodating hydrophobic signals via induced fit. Binding transiently arrests elongation, complex diffuses to ER membrane where heterodimeric SRP receptor composed of SR alpha and SR beta, both GTPases, docks particle. GTP

Ref: Walter Nature 1981 SRP discovery; SRP54 binds signal peptide, GTP-dependent delivery to Sec61.

View Details

Protein Sorting and Trafficking

Which signal is necessary for targeting soluble lysosomal enzymes?

Among diverse sorting determinants mannose-6-phosphate uniquely marks entire class of soluble lysosomal precursors enabling intracellular lysosome biogenesis. Newly synthesized acid hydrolases enter ER lumen, receive high-mannose N-glycans via oligosaccharyltransferase, fold with calnexin, move to cis-Golgi where Golgi-resident phosphotransferase adds M6P as phosphodiester then uncovered in TGN to yield exposed phosphate. Carbohydrate address recognized in TGN pH 6.7 by two M6P receptors both P-type lectins: 300 kDa cation-independent IGF2 receptor binding also IGF2 and 46 kDa cation-dependent

Ref: Lodish et al., MCB: Mannose-6-phosphate signal targets soluble lysosomal enzymes to lysosomes.

View Details

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 GTP

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

View Details

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 cata

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

View Details

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 do

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

View Details

Protein Sorting and Trafficking

Which transport mechanism does NOT require a signal sequence?

Small metabolites, ions, nucleotides and proteins smaller than roughly 40 kilodaltons equilibrate between nucleus and cytoplasm without peptide targeting signals because the nuclear pore complex forms a large aqueous channel about nine nanometers wide lined with intrinsically disordered FG-repeat nucleoporins that act as a size-selective hydrogel sieve allowing diffusion along concentration gradients. This passive process supports rapid exchange of ATP, GTP, amino acids and small second messengers needed for transcription, DNA replication and growth, without consuming energy. By contrast, larg

Ref: Alberts et al., Molecular Biology of the Cell, 6th ed., Chapter 12: Nuclear Pore Complex and Passive Diffusion of Small Molecules.

View Details