PeptideNo peptideWhen T cells recognize virus-infected cells, what they’re actually “recognizing” is a short peptide that’s stuck in a class I major histocompatibility complex. The peptide sits neatly in a groove formed by two helices on top of a beta-sheet (“a hot dog in a bun”, students are told in immunology class, though to me it doesn’t look much like that).1 On the left, there’s a diagram of this groove with no peptide associated — on the right, with its peptide tucked in — and below, there’s a space-filling view (from a different angle, but till looking “down” at the MHC surface, the way a T cell would be “looking”). In this last view I’ve made the MHC atoms outline; the peptide is in brown, so you can see how tightly packed the peptide is. The “groove” is a pocket as much as a groove, and the peptide is buried fairly deeply within that pocket, with only its top surface exposed for T cells to look at. KbSIEFARL

How does the peptide wiggle into that slot? You can imagine that it would have some trouble just clicking in, like a Lego (TM) piece. What probably happens normally is that the pocket in the MHC is held in a more open configuration (the MHC class I is partially but not completely folded) until the peptide starts to settle in, and then the MHC actually finishes folding around the peptide. (There’s only circumstantial evidence for this, but it’s always hard to look at folding intermediates directly, even when they’re relatively long-lasting.) You’d expect that an accessory molecule, or molecules, might be involved either in the “holding open” phase, or in the “folding around the peptide” phase, or both.

As it happens, MHC class I interacts with a bunch of proteins during its maturation in the ER — classical chaperones like BiP, calnexin, calreticulin, ERp57, and PDI, ambiguous chaperones like tapasin, and the peptide transporter TAP. Of this list, tapasin has been the strongest candidate for “holding open” MHC class I and keeping it in a peptide-receptive state, and the finding that tapasin and ERp57 interact offered some conceptual models for how this might work.The latest issue of Nature Immunology has a paper that clarifies this:
Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer
Pamela A Wearsch & Peter Cresswell
Nature Immunology (Advance Online Publication: doi:10.1038/ni1485)

Cresswell’s group has finally managed to reconstitute peptide loading of MHC class I in vitro. There have been lots of attempts at this, but none have worked well. 2 The key turns out to be that tapasin alone doesn’t work; you need to include a tapasin-ERp57 disulphide-linked heterodimer. (Calreticulin was also part of the complex they used, though it’s not clear to me whether that was essential for loading.)Under these conditions, tapasin/ERp57 acts as a “peptide editor”, in that when tapasin/ERp57 is present low-affinity peptides are less able to compete for binding — in other words, tapasin/ERp57 helps assure that the peptides associated with MHC class I are “good” ones. Apparently the tapasin/ERp57 heterodimer directly competes with peptides for binding: 3

This observation suggests that the mechanism underlying peptide editing involves a reiterative process in which peptide displaces conjugate and conjugate displaces peptide until a sufficiently high affinity is reached that peptide remains associated.

This seems remarkably similar to the function of HLA-DM in MHC class I peptide assembly.

  1. 2007 is, I believe, the 20th anniversary of the first MHC class I crystal structure, and I’ll spend more time going over some of the more exciting features in a later post.[]
  2. Peptide will associate with a purified MHC class I/beta-2-microglobulin complex in the test tube, but it’s a very slow process, hours to days, compared to the 10-30 minutes that it takes in vivo.[]
  3. I don’t think this implies they necessarily bind to the same site, though.[]