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Experimental Biology 2008, Part 2
- NKG2D, my favorite immunoreceptor, is implicated in a mouse hepatitis model and liver cancer as well. An NKG2D domain stuck onto a CD3 tail inside the cells makes for T cells that attack and destroy ovarian tumors in mice.
- In the strange connections between projects department: dimethyldisulfide (very close in structure to diallyl disulfide from our garlic project) is associated in mice with particular MHC molecules (very similar to the MICA proteins I study). It’s how mice can “smell” whether a potential mate has a compatible immune system or not. Weird.
- Rats have molecules like MICA too, and after a liver transplant they pop up all over the liver and may play a role in transplant rejection.
- Walter Englander spoke about hydrogen exchange. He doesn’t agree with the “everything at once” school of protein folding but thinks folding happens in discrete steps. This means folding is not so much a smooth funnel as a mountainside with rivulets (and pools) running down it. The steps of folding are foldons, sequentially stabilized units. One basic kind of foldon is probably the N- and C-termini coming together and forming a surface that the rest of the protein builds off of. Ten years from now he predicted that we’ll be sitting at a conference talking about foldons and how they relate to on/off rates, structural changes, equilibria, etc. Well, I’m interested in the idea because right now MICA sure looks like it’s got an incomplete foldon at the binding surface that depends on the presence of NKG2D to complete. Is this why we got our unexpectedly increased on-rates? Hopefully in 10 years I’ll have something to say about it. In the meantime I hope to figure out how to get access to an LC-MS so I can try HX. (Also, this just occurred to me: what’s the relationship between Englander’s foldons and Schreiber’s binding modules? Both are determined by cooperativity, after all.)
- RosettaDesign’s new “backrub” function looks possibly useful for resolving our current problem with the tryptophan mutant. If it doesn’t work, then it means larger-scale motions are responsible for the good binding.
- An ensemble view of proteins was presented that seems a good explanation for how communication through cooperativity happens, and why it’s so hard to nail down a specific pathway sometimes: because cooperativity may often be an attribute of the entire ensemble of states, not just amino acids lined up like dominos. It’s an example of how order can emerge from random mutations.
- Then some single molecule studies were presented for pulling apart proteins with optical tweezers. It’s fun to watch the proteins fold and unfold. Also, note it's how GroEL works, by pulling the protein apart and giving it another chance to refold. GroEL is a merciful protein!
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1 comment:
Peter Wolynes has this idea that proteins can have localized frustration, or contacts in the folded that are not ideal. One could map all the contacts throughout a protein and determine their relative frustration (a frustogram - not my word :) ). Perhaps MICA is frustrated at its contact interface, stuck in a higher energy, near-native fold? Upon binding NKG2D this frustration is relieved, and MICA stabilizes to a lower energy fold. So the fast on rate is partially due to the fact that upon binding, MICA becomes less frustrated. I wonder, how hydrophobic is the MICA contact surface? Maybe that would contribute as well - favorable entropy upon binding?
Did you ever do any HD exchange? I think its a very neat tool - perhaps you could use it to probe the MICA-NKG2D interaction. Although my professor thinks that Englander might be a little too simplistic in the way that he approaches exchange (ie, he thinks that there are only two types of exchange: fast or slow. But what about intermediate exchange speeds, whats going on and what does that tell you about the structure?)
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