Membrane protein biogenesis: Type I integral plasma membrane proteins are characterized by which signal/anchor arrangement during co-translational insertion into the ER membrane?
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ACleavage N-terminal signal sequence and a hydrophobic stop-transfer sequence
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BCleaved N-terminal signal sequence that also serves as the membrane anchor
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CMultiple signal sequences and one hydrophobic stop-transfer sequence only
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DMultiple signal sequences that double exclusively as anchors without stop-transfer segments
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ENo signal sequence; post-translational spontaneous insertion
Answer
Correct Answer: Cleavage N-terminal signal sequence and a hydrophobic stop-transfer sequence
Explanation
Introduction:Integral membrane proteins use topogenic signals to achieve correct orientation. Type I single-pass proteins have an N-terminal lumenal domain and a cytosolic C-terminus. Understanding how signal peptides and stop-transfer sequences coordinate insertion is essential for predicting topology from sequence.
Given Data / Assumptions:
- Secretory pathway uses the signal recognition particle (SRP) and Sec61 translocon.
- Signal peptides direct ribosome–nascent chains to the ER; signal peptidase can cleave them.
- Hydrophobic segments can halt translocation and become transmembrane helices.
Concept / Approach:Type I proteins begin with an N-terminal signal peptide that is cleaved in the ER lumen. Downstream, a hydrophobic stop-transfer sequence exits the lateral gate of the translocon to become the membrane-spanning helix, anchoring the protein with N-terminus in the lumen and C-terminus in the cytosol. This combination—cleaved signal peptide plus stop-transfer anchor—defines Type I topology.
Step-by-Step Solution:
Signal peptide emerges from the ribosome, binds SRP, and targets the complex to the ER membrane.Insertion through Sec61 begins; signal peptide is cleaved by signal peptidase in the lumen.A downstream hydrophobic segment acts as a stop-transfer sequence and partitions into the lipid bilayer.Translocation stops; the remainder of the protein is synthesized on the cytosolic side, producing Type I orientation.Verification / Alternative check:Protease protection assays and glycosylation mapping confirm N-lumenal/C-cytosolic orientation for Type I proteins; mutational loss of the stop-transfer helix disrupts membrane anchoring.
Why Other Options Are Wrong:
- Signal as anchor itself (option b): true for signal-anchor (Type II/III), not Type I.
- Multiple signals without stop-transfer: describes multi-pass topologies, not canonical Type I.
- No signal sequence: most Type I proteins rely on SRP-dependent targeting.
Common Pitfalls:Confusing Type I (cleaved signal + stop-transfer) with Type II/III (internal signal-anchor) or assuming all hydrophobic stretches are equivalent in topogenesis.
Final Answer:Cleavage N-terminal signal sequence and a hydrophobic stop-transfer sequence