63. A ligand recognizes two different cell surface receptors. A and B, on the same cell type. Receptor A. after with the ligand internalized along with the ligand whereas receptor B, after binding with the ligand, initiates tyrosine kinase activity of the intracellular domain. One particular disease is associated with the loss of receptor-mediated signal transduction of the ligand. Different observers inferredthat the disease may be resulted due to
A. loss of binding affinity of receptor A due to mutation in the extracellular domain.
B. loss of binding affinity of receptor B due to mutation in the extracellular domain.
C. mutation in the tyrosine kinase domain rendering it inactive.
D. mutation in the intracellular domain rendering it incapable of endocytosis.
Which combination of the above inferences doyou think is appropriate for the cause of the disease?
(1) A and B          (2) B and C
(3) C and D          (4) A and D

Disease Mechanisms Involving Two Receptor Types: Internalizing Receptor A and Tyrosine Kinase Receptor B

Overview

A ligand binds two different receptors, A and B, present on the same cell. Receptor A internalizes along with the ligand, whereas receptor B initiates tyrosine kinase activity upon ligand binding. A disease is linked to defective receptor-mediated signaling of this ligand.

Understanding the Problem

• Receptor A: Loss of function could arise if its extracellular domain mutates, reducing ligand binding, thus impairing ligand uptake.

• Receptor B: Loss of function may stem from extracellular domain mutations leading to poor ligand binding or from intracellular tyrosine kinase domain mutations rendering it inactive.

• Intracellular domain mutations in receptor A affecting endocytosis might also prevent ligand internalization and signaling.

Evaluating the Causes

• Option A: Mutation in extracellular domain of receptor A causing loss of ligand binding — highly plausible.

• Option B: Mutation in extracellular domain of receptor B causing loss of ligand binding — also plausible.

• Option C: Mutation that inactivates the tyrosine kinase domain of receptor B — directly affects signaling capability and is a common disease mechanism.

• Option D: Mutation in intracellular domain of receptor A affecting endocytosis — would impair ligand internalization pathway.

Appropriate Disease Causes

• A and D: Both affect receptor A’s ligand uptake.

• B and C: Both affect receptor B’s ability to bind and signal.

Because the disease is linked to defective signal transduction of the ligand, impairments in receptor B’s signaling (B and C) are critical causes. Similarly, defects in receptor A’s ability to internalize ligand (A and D) also contribute.

Correct Combination Choice

• (1) A and B

• (2) B and C

• (3) C and D

• (4) A and D

From the biological and mechanistic perspective, the best answer is (2) B and C, emphasizing the signaling receptor B’s dysfunction (loss of ligand binding and inactive kinase domain) as a disease cause.

---