​Iron (Fe) is taken up by cells via receptor-mediated endocytosis utilizing transferrin and transferrin receptor. In a cell line with a mutation in the transferrin receptor that is unable to interact with transferrin at pH 4-6, which one of the following steps will be first affected in this pathway?

Correct option is D

​The transferrin receptor mutation that prevents interaction with transferrin at pH 4-6 affects the recycling of transferrin to the plasma membrane . Normally, iron-bound transferrin (holo-transferrin) binds to the transferrin receptor (TfR) at the cell surface and is internalized via receptor-mediated endocytosis. In the acidic environment of the endosome (pH ~5.5), transferrin undergoes a conformational change that reduces its affinity for iron, facilitating its release into the cytoplasm.

Information Booster:

1. Transferrin is a glycoprotein responsible for iron transport in the blood.
2. Iron uptake occurs via receptor-mediated endocytosis, where transferrin binds to transferrin receptor (TfR) on the cell surface.
3. Endosomal acidification (pH ~5.5) induces iron release, allowing free iron to enter the cytoplasm.
4. The transferrin receptor then recycles to the plasma membrane, returning apo-transferrin (iron-free transferrin) to the extracellular space.
5. Mutations in TfR can cause iron-related disorders, such as anemia due to defective iron uptake.
6. Iron is essential for cellular functions, including DNA synthesis, respiration, and metabolism.

Additional Knowledge:

(a) Binding of transferrin to iron in plasma:

• Iron exists in two forms in plasma: Fe²⁺ (ferrous) and Fe³⁺ (ferric).
• Transferrin binds Fe³⁺ with high affinity at physiological pH (~7.4).
• This step occurs independently of the transferrin receptor and is not affected by receptor mutations.

(b) Association of iron-bound transferrin with transferrin receptor on the plasma membrane:

• The transferrin receptor (TfR) is a type II transmembrane glycoprotein that binds transferrin.

(c) Release of iron in the endosomes:

• Once internalized, the transferrin-TfR complex enters early endosomes.
• Acidification of the endosome (pH 5-6) triggers conformational changes in transferrin, reducing its affinity for Fe³⁺.

(d) Recycling of transferrin to the plasma membrane (correct answer):

• After iron release, apo-transferrin (iron-free transferrin) remains bound to TfR and recycles to the plasma membrane.
• In a cell line with a mutation in the transferrin receptor that is unable to interact with transferrin at pH 4-6, transferrin will not bind with transferrin receptor again and the receptor will recycle to plasma membrane alone without transferrin.
• At neutral pH (extracellular), apo-transferrin dissociates from TfR and reenters circulation.