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Answer by Tirumalai Kamala:

I’ll start with a few definitions to help a general reader.

Definitions
Anchor residues are “conserved positions in a peptide repertoire for a given MHC allele that “anchor” the peptide in the MHC groove” (1).
MHC Isotype: A particular MHC locus. HLA-A, -B, or -C are three classical MHC class I loci.
MHC Allotype: Alleles, i.e., genetically distinguishable forms of the molecule.

MHC class I molecules are classified as classic (for example HLA-A, -B, -C in human) and non-classical (for example HLA-G, -E in human)

Classical MHC class I molecules, HLA-A, B, C (human); H2-K, D, L (mouse)
Classical MHC class I molecules are highly polymorphic, which enables them to bind and present a wide variety of peptides to the ab receptor of T cells, preferentially CD8+ T cells. Most MHC class I molecules bind octamers (peptides that are 8 amino acids in length) or nonamers (9 amino acid length peptide). Each MHC molecule is theoretically capable of binding thousands of different peptides. How could it do that? Each MHC molecule has a peptide-binding groove. Peptides get bound in this groove like a hot dog in a hot dog bun. Can any random peptide bind an MHC peptide binding groove? No, certain positions in an MHC molecule’s peptide binding groove are very restricted in the choice of amino acids they bind. They are called anchor positions, and they ensure that out of the thousands of peptides available from intra-cellular protein degradation and digestion, only specific sequences get bound and presented by a specific MHC class I allele. In 1991, Falk et al defined an anchor position as one “occupied by a fixed residue or by one of a few residues with closely related side chains” (2). Their study found anchor positions at 5 and 9 for H2-Db, 2 and 9 for H2-Kd, and 5 and 8 for H2-Kb, H2-Db, H2-Kd and H2-Kb being mouse classical MHC class I molecules. In humans, HLA-A*02:01 represents the canonical archetype with anchor positions at 2 (Leucine and Methionine preferred) and 9 (Valine, Leucine, Isoleucine and Methionine preferred).

So, which class I MHC molecules anchor peptides at positions other than 2 and the last?

This table is from the online resource, Statistics. 9, 437 alleles? That’s a lot!

I suggest to browse through this handy online resource to find those that anchor at  positions other than 2 and the last. Take HLA-B*08:01 for example, which anchors at 5 and 9.

From the online resource, MHC Class I Allele B restricted epitopes

You can browse by allele here: Browse By MHC Allele

As you browse through, you will also find that anchor positions have not yet been mapped for many MHC alleles.

The picture is different with HLA-C, -E, and -G. HLA-C is the most recently evolved classical HLA class I isotype (3, 4), being present only in hominids. When Rasmussen et al (5) did a detailed analysis of peptide-binding specificity of HLA-C allotypes in 2014 (5), they found “HLA-C*14:02 has a very unusual and promiscuous binding motif with no clear P2 or P3 anchor residues and only a weak P9 primary anchor”.

From 5
Thus,  HLA-C*14:02 is a newly discovered example of a classical MHC class I molecule with non-canonical anchor positions.

Non-classical MHC class I molecules. HLA-E, -G in human; Qa-1, and -2 in mouse
HLA-E (human)
The fun thing about HLA-E is what it presents, peptides derived from leader sequences of other MHC class I molecules! Signal peptidases cut the signal sequence of classical MHC molecules, and their hydrophilic N-terminus portions are released into the cytosol where they are processed by the proteasome, resulting in a leader peptide (6), which binds the peptide-binding groove of HLA-E.
Unlike classical MHC class I molecules, HLA-E has 5 anchor positions, at 2, 3, 6, 7 and 9 (1, 7, 8, 9, 10).

From 11

HLA-G (human)
HLA-G is very restricted in expression, being largely confined in humans to fetal extravillous trophoblasts in the placenta. While HLA-G has a more promiscuous peptide-binding capacity compared to HLA-E, its peptide repertoire is much more restricted because of its placenta-specific expression.
HLA-G has 3 anchor positions, at 3, 4, 9 (1).

Qa-1 (mouse)
Like HLA-E, Qa-1 preferentially presents leader sequence peptides derived from other MHC class I molecules, and also has the same 5 anchor positions, at 2, 3, 6, 7 and 9 (1).

From 11

Qa-2 (mouse)
Qa-2 is the functional homolog of HLA-G (1) and has 3 anchor positions, at 2, 3, 9.

Bibliography

  1. Adams, Erin J., and Adrienne M. Luoma. “The adaptable major histocompatibility complex (MHC) fold: structure and function of nonclassical and MHC class I-like molecules.” Annual review of immunology 31 (2013): 529-561
  2. Page on uiowa.edu
  3. Page on nih.gov
  4. Chimpanzees Use More Varied Receptors and Ligands Than Humans for Inhibitory Killer Cell Ig-Like Receptor Recognition of the MHC-C1 and MHC-C2 Epitopes
  5. A General Strategy To Determine the Specificity of Any MHC Class I Molecule
  6. Page on intechopen.com
  7. Page on els-cdn.com
  8. HLA-E Allelic Variants
  9. Hoare HL, Sullivan LC, Pietra G, Clements CS, Lee EJ, Ely LK, et al. Structural basis for a major histocompatibility complex class Ib-restricted T cell response. Nat Immunol 2006;7:256.
  10. Page on nih.gov
  11. A Structural Basis for Antigen Presentation by the MHC Class Ib Molecule, Qa-1b

Which Class I MHC alleles have “non-canonical” anchor positions (other than the 2nd and last peptide positions)?

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