Membrane protein biogenesis: Type I integral plasma membrane proteins are characterized by which signal/anchor arrangement during co-translational insertion into the ER membrane?

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:

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