Q.40 Peptide–binding cleft in MHC–I is formed by
(A) 𝛼1 and 𝛼2 domains.
(B) 𝛼1 and 𝛼3 domains.
(C) 𝛼1 domain and 𝛽2–microglobulin.
(D) 𝛼2 domain and 𝛽2–microglobulin.

The peptide-binding cleft in MHC class I molecules is formed by the α1 and α2 domains of the heavy chain. This structure is critical for presenting intracellular peptides to CD8+ T cells during immune surveillance.

Question Analysis

MHC class I molecules consist of a polymorphic α-chain (with α1, α2, and α3 domains) non-covalently associated with β2-microglobulin. The peptide-binding cleft, or groove, accommodates 8-10 residue peptides and is formed specifically by the membrane-distal α1 and α2 domains folding into a β-sheet floor topped by two α-helices.​

Option Breakdown

• (A) α1 and α2 domains: Correct. These domains create the peptide-binding groove through their structural interaction, enabling peptide anchoring at both ends via conserved pockets (A and F pockets).​

• (B) α1 and α3 domains: Incorrect. The α3 domain is an Ig-like structure that interacts with CD8+ T cells and β2-microglobulin but does not contribute to the peptide cleft.​

• (C) α1 domain and β2-microglobulin: Incorrect. β2-microglobulin stabilizes the overall MHC I structure and supports the α3 domain but plays no direct role in forming the cleft.​

• (D) α2 domain and β2-microglobulin: Incorrect. While the α2 domain forms one helix of the groove, β2-microglobulin is distant from the binding site and aids platform stability instead.​

The peptide-binding cleft in MHC class I (MHC-I) serves as the key site for antigen presentation, binding short peptides (8-10 amino acids) derived from intracellular proteins to alert cytotoxic T cells. Understanding its formation by α1 and α2 domains is essential for exams like CSIR NET Life Sciences, where questions test MHC structure and function.

MHC Class I Structure Overview

MHC-I molecules are heterodimers comprising a heavy α-chain (~45 kDa) with three extracellular domains (α1, α2, α3), a transmembrane region, and non-covalent β2-microglobulin (~12 kDa). The peptide-binding cleft in MHC-I arises from the α1 (N-terminal, ~90 residues) and α2 domains folding into an open-ended groove: a platform of eight antiparallel β-strands flanked by two α-helices. This architecture anchors peptides via hydrogen bonds at the N- and C-termini.​

Role of α1 and α2 Domains

The α1 domain contributes the N-terminal helix and β-strands, while α2 provides the C-terminal helix. Together, they form the closed-ended cleft specific to MHC-I (unlike the open-ended MHC-II groove). Polymorphism in these domains dictates peptide specificity, crucial for immune recognition.​

• α1: Forms A-pocket for peptide N-terminus.

• α2: Forms F-pocket for C-terminus and influences T-cell receptor contact.

Why Not Other Components?

β2-microglobulin stabilizes the platform by associating with α3 (Ig-like domain for CD8 binding), but mutations here disrupt folding without affecting the cleft directly. α3 interacts with CD8 but lies below the groove.​

Exam Relevance for CSIR NET

In MCQs like “Peptide-binding cleft in MHC-I is formed by,” option (A) α1 and α2 domains is standard. Compare with MHC-II (α1 + β1 domains) to avoid confusion.​