I talk a lot about MHC molecules, especially MHC class I. Something I haven’t mentioned much is that MHC class I is just one member of a huge extended family of structurally-related molecules. MHC class I and class II are the “classical” MHCs (the Archie Bunker and Edith of histocompatibility complexes); but there’s a long list of spin-off “non-classical” MHCs as well. 1 Many of them are solid citizens that conscientiously perform immune-related tasks, but there are also some whacky neighbours that run around doing zany stuff.

Last week I covered the structure of MHC class I (the Bjorkman structure of HLA-A2). For comparison, here’s a superficial glance at the comparative anatomy of a number of classical and non-classical MHCs. The structural similarity is often pretty remarkable, considering the variety of things they do — iron-regulatory molecules, odor detection, and antigen presentation, for a start! In general, the two things I look at structurally are whether they bind to β2-microglobulin, and what their equivalent of a peptide-binding groove looks like. (Because I’m mostly emphasizing the peptide-binding groove in these images, β2-m is often hard to see, hidden as it is underneath the floor of the groove. If you squint, you can see it — it’s colored blue in the ribbon structures — except for ZAG and MHC class II, which don’t have it at all.)

The molecules (along with their Protein Database accessions, and the Pubmed ID of the article describing their structure) I’ve chosen are as follows:

MHC Family Role Groove binds β2-m PDB PMID
HLA-A2 (MHC class I) Classical Antigen presentation Peptide Yes 2GTW 10843695
HLA-DR (MHC class II) Classical Antigen presentation Peptide No 1DLH 8145819
HLA-E Non-classical NK cells recognition Peptide Yes 1MHE 9660937
CD1d Non-classical Non-classical T cell recognition Lipglycans Yes 2GAZ 16982895
FcRn (Neonatal Fc receptor) Non-classical Neonatal Fc receptor Nothing Yes 1EXU 10933786
ZAG (Zinc-α-2-Glycoprotein) Non-classical Lipid catabolism Something (what?) No 1ZAG 10206894
HFE Non-classical Iron regulation Nothing Yes 1A6Z 10638746
Qa2 Non-classical Immune regulation? Peptide Yes 1k8d 11738047
M10.5 Non-classical Odor receptor chaperone? Nothing? Yes 1ZS8 16089503

First of all, let’s look at some of the guys who bind stuff in their groove (click on each image for a larger version). Here we are, looking “down” from the top of the molecule (as the T cell would looks at HLA-A2, for example) — a surface representation of the MHC molecule with its ligand shown in green. In the lower row, I show the ligand all by itself, as it sits in the groove.

HLA-A2 HLA-DR HLA-E Qa-2 CD1d
HLA-A2 peptide HLA-DR peptide HLA-E peptide Qa-2 peptide CD1d Ligand
MHC class I MHC class II HLA-E Qa-2 CD1d

The odd one out is CD1d, which binds non-peptides — here, a Mycobacterium tuberculosis phosphatidylinositol mannoside. The CD1 binding groove is much deeper and more hydrophobic than that of the peptide-binders’: a tunnel, in places, rather than a groove. Another difference is between MHC class II (HLA-DR in this picture) and most of the other peptide binders; MHC class II peptides can flop out over the edges of the groove (whereas the other guys bury the ends of the peptide) — so MHC class II peptides can be quite a bit longer than the 9 or so amino acids that other MHCs can handle.

Next let’s look at the rest of the crew — the ones that don’t bind peptides, or perhaps anything, in their grooves. For ease of comparison I’m including MHC class I (HLA-A2) again, at the left. In the lower row, I’m showing the same views as ribbon diagrams.

HLA-A2 FcRn ZAG HFE M10.5
HLA-A2 FcRn ZAG HFE M10.5
MHC class I FcRn ZAG HFE M10.5

(Notice that ZAG doesn’t have any β2-m associated with it, but nevertheless forms a very nice binding groove.) You can see very easily for FcRn that the groove is completely screwed up: it’s collapsed and filled in, so there’s nowhere for a peptide, or even a much smaller molecule, to fit in. It’s harder to see for HFE, but the groove there is still too narrow to bind peptides (though it’s not completely collapsed). ZAG and M10.5 are much more interesting. Both have grooves that could actually hold something, but we don’t know what (if anything) they bind.

ZAG binding With ZAG, something actually co-crystallized with the molecule! –but they don’t know what it is. ” … Instead of a peptide, the ZAG groove contains an as yet unidentified ligand that cocrystallizes with the protein.”2 (The figure at right clearly shows something undefined in the ZAG binding groove.)

M10.5 was equally interesting (in the “incident of the dog in the night” sense) — because, even though the groove could actually potentially hold a peptide3 nothing at all was in the crystallized groove. This never happens with classical MHC molecules, which always find something to bind there. But the groove seems (biochemically as well as structurally) to be a complete blank.

M10.5 has an open groove more similar to the peptide-binding classical class I MHC molecules than the non-peptide-binding homologs. … M10.5 electron-density maps show no ordered density corresponding to a peptide … We conclude that the M10.5 groove does not contain a single defined peptidic or non-peptidic occupant or a mixture of compounds with a similar conformation.4

Given that M10.5 seems to be involved in odor recognition — Could it be a pheremone binder? Sadly (because that would be a great story), probably not: “The hydrophobic nature of most pheromones is not complementary to the charged character of the groove, which is much larger than a single pheromone molecule.”

Their final guess is that maybe M10.5 chaperones a V2R — a different receptor:

In this hypothesized scenario, newly synthesized M10 and V2R proteins would be stabilized through mutual interactions with a V2R loop in the M10 groove, enabling the M10 to escort the V2R to the cell surface, rationalizing the observation that M10 proteins are required for cell surface expression of V2Rs. 4

Anyway, there’s a field guide to some of the MHC family. There are many, many more, each with its own beautiful plumage and habitat, but these cover most of the general variations in structure you’ll see.


  1. Actually, many of the “non-classicals” are just about as ancient as the “classical” MHCs, so it’s not really clear which is the spin-off. But I liked the metaphor.[]
  2. Sanchez, L. M., A. J. Chirino, and P. Bjorkman. 1999. Crystal structure of human ZAG, a fat-depleting factor related to MHC molecules. Science 283: 1914-1919. []
  3. “We conclude that the M10.5 groove can accommodate a peptide that adopts a class I MHC-binding conformation, but that differences between the A and F pocket regions of M10.5 and classical class I MHC molecules would require a peptide bound in the M10.5 groove to be anchored differently than a class I MHC-binding peptide”[]
  4. Olson, R., K. E. Huey-Tubman, C. Dulac, and P. J. Bjorkman. 2005. Structure of a pheromone receptor-associated MHC molecule with an open and empty groove. PLoS Biol 3: e257.[][]