E1 conformational changesYeah, so this is getting a little repetitious. The new E1 I noted back in June, and then again in August, has been reported one more time.

Whining aside,1 the new paper2 is a nice addition to the pack, because it offers a quick look at a knockout mouse, and a new binding partner.

The significance of a new E1, if you don’t want to look at my previous posts, is that E1s are the upstream-most enzyme involved in the ubiquitin cascade,3 which is critical to all kinds of cellular function starting from (but not limited to) regulated proteolysis . It had been believed that there was only a single E1 enzyme in most mammalian genomes, although the downstream enzyme families E2 and E3 are much more variable (a couple dozen genes, and close to a thousand, respectively). Jin et al4 and Pelzer et al5 both identified a new E1 (Jin et al called it UBA6; Pelzer et al stuck to an established name and called it UBE1L2) and showed that it is capable of charging ubiquitin but not any of several other ubiquitin-like substrates. Jin et al took it a little further, showing, for example, that the E1 did have a specific E2.

Chiu et al call the gene E1-L2, which is near as dammit to the authentic name but just different enough that I had to compare sequences to make sure it was the same.6 As well as ubiquitin, they do find a different substrate for E1-L2: the ubiquitin-like molecule FAT10, which had been specifically ruled out by the other groups (Chiu et al explain it as a techinical problem with the system,7 which I don’t know well enough to comment on).

The knockout mouse is embryo-lethal, which was already known though not, I think, published (thanks to Jianping Jin for sending me some unpublished info a while back). This is in contrast to FAT10 knockout mice, which are viable and not grossly abnormal,8 so E1-L2/UBE1L2/UBA6 does something else — consistent with a role for this thing in authentic ubiquitination pathways.

The connection with FAT10 makes this thing even more interesting to me, because FAT10 is encoded in the major histocompatibility complex — a region that contains many genes important in immunity — and FAT10 has been linked to some aspects of the immune response.

  1. But before I stop whining, doesn’t Molecular Cell use DOIs? I can’t find one associated with the paper. Get with the new millennium, guys![]
  2. E1-L2 Activates Both Ubiquitin and FAT10. Yu-Hsin Chiu, Qinmiao Sun, and Zhijian J. Chen. Molecular Cell, Vol 27, 1014-1023, 21 September 2007 []
  3. (The figure at top, taken from VanDemark, A. P., and Hill, C. P. (2005). E1 on the move. Mol Cell 17, 474-475. , shows a model of E1’s mechanism of action.[]
  4. Dual E1 activation systems for ubiquitin differentially regulate E2 enzyme charging. Jianping Jin, Xue Li, Steven P. Gygi & J. Wade Harper. Nature 447, 1135-1138 (28 June 2007) []
  5. UBE1L2, a Novel E1 Enzyme Specific for Ubiquitin. Christiane Pelzer, Ingrid Kassner, Konstantin Matentzoglu, Rajesh K. Singh, Hans-Peter Wollscheid, Martin Scheffner, Gunter Schmidtke, and Marcus Groettrup. J. Biol. Chem., Vol. 282, Issue 32, 23010-23014, August 10, 2007 []
  6. They make it clear in their discussion, so I should have read the whole paper before grumbling.[]
  7. “We believe it is important to remove the GST tag or replace it with a smaller tag such as His6 in order to observe the activation of FAT10 by E1-L2.”[]
  8. FAT10/diubiquitin-like protein-deficient mice exhibit minimal phenotypic differences. Canaan, A., Yu, X., Booth, C. J., Lian, J., Lazar, I., Gamfi, S. L., Castille, K., Kohya, N., Nakayama, Y., Liu, Y. C., Eynon, E., Flavell, R., and Weissman, S. M. (2006). Mol Cell Biol 26, 5180-5189. []