Protein targeting: Removal of the N-terminal signal peptide from a protein translocated across the membrane is catalyzed by which enzyme?

Introduction:
Secretory and many membrane proteins begin with an N-terminal signal peptide that targets the ribosome–nascent chain to the translocon (e.g., Sec61 in the ER or SecYEG in bacteria). After insertion or translocation starts, the signal sequence is cleaved off by a dedicated enzyme to generate the mature N-terminus. Identifying this enzyme is key to understanding co-translational targeting and maturation.

Given Data / Assumptions:

• Signal peptides are short, hydrophobic N-terminal sequences with identifiable cleavage motifs.
• Cleavage occurs in or near the lumenal/periplasmic side as the chain emerges through the channel.
• General proteases like trypsin/chymotrypsin have broad specificity but are not the physiological signal peptide processing enzymes.

Concept / Approach:
Signal peptidase (also called leader peptidase) recognizes specific small-residue motifs at the signal peptide–mature junction and cleaves the peptide bond to release the signal and expose the new N-terminus of the protein. This processing is distinct from removal of an initiator methionine (by methionine aminopeptidase) or from trimming of formyl groups in bacteria (by peptide deformylase). The specialized topology and localization of signal peptidase allow precise co-translational cleavage.

Step-by-Step Solution:

Verification / Alternative check:
Mutations in signal peptidase or in signal peptide cleavage motifs cause accumulation of uncleaved precursors and secretion defects, confirming the enzyme's specific role.

Why Other Options Are Wrong:

• fMet aminopeptidase: removes initiator Met (or formyl-Met), not signal peptides.
• Trypsin/chymotrypsin: broad proteases used experimentally, not the physiological signal-cleaving enzyme.
• Peptidyl–prolyl isomerase: catalyzes cis–trans proline isomerization, unrelated to signal cleavage.

Common Pitfalls:
Confusing general proteases with the membrane-embedded signal peptidase or mistaking initiator methionine removal for signal peptide processing.

Final Answer:
Signal peptidase