Alex Palazzo is an Assistant Professor in the Department of Biochemistry at The University of Toronto.
Monday I saw an incredible lecture by U. Wash's Ning Zheng. (Yes Bil, I actually enjoyed a structure biology talk!)
I'll just summarize Dr. Zheng's last paper that was on the cover of the April 5th edition of Nature.
Intense studies on phototaxis in plants that began in part by Darwin (yup, that's right) led to the discovery of auxin, a diffusible signal that stimulates growth in plant cells. How do cells sense the growth factor? No one could identify the receptor until recently. It was known that auxin treatment promoted the degradation of the Aux/IAA transcription silencer, a protein that inactivates genes that are critical for cell growth.
It turns out that auxin binds to a pocket in the a ubiquitin ligase complex (TIR1-ASK1) and
By filling in a hydrophobic cavity at the protein interface, auxin enhances the TIR1-substrate interactions by acting as a 'molecular glue'.
In other words auxin helps TIR1-ASK1 to bind to substrates like Aux/IAA by bridging a gap between the enzyme and the substrate. Thus Aux/IAA becomes ubiquitinylated by TIR1-ASK1 and then degraded. A century old problem is solved (at the molecular level).
An interesting new paradigm: a small molecule that helps protein-protein interactions. Think of of it. All these chemical biologists are hunting for proteins that inhibit enzyme activity or disrupt protein-protein interactions, but perhaps they should be looking for the opposite. This is true when dealing with mutant enzymes that can't bind to their proper substrates. Perhaps we can fix these enzymes with molecular glue - i.e. small molecules that enhance a mutant protein's ability to recognize its proper substrate.
But wait there is more. Just like auxin, IP6 binds to a pocket between TiR1 and the substrate ...yes IP6 acts as a second patch of molecular glue.
Lets list where IP6 has been turning up recently.
- IP6 stimulates Gle1's ability to activate the RNA helicase activity of Dbp5, and is thought to promote Dbp5's ability to facilitate RNA export from the nucleus. See this link for more.
- IP6 is a cofactor for ADAR, a protein that recognizes double stranded RNA in the nucleus and then converts adenosines found in the dsRNA to inosine.
- IP6 also activates DNA-PK, a protein kinase that recognizes and helps repair double-stranded DNA breaks.
Interestingly, IP6 is often associated with enzymes that deal with nucleic acids ... except in the TIR1-ASK1 complex.
So is IP6 a signaling molecule?
Well there is apparently a lot of IP6 in us, but it keeps on popping up where we least expect it.
Comments
I dunno, I wouldn't call that a new paradigm. That small molecules can make proteins locally fold/refold is the basis of ordered sequential enzyme kinetics. That they can have effects on distal protein structure and protein-protein binding sites is the basis of cell-surface receptor function.
Or, think periplasmic binding proteins. They bind a small molecule, be it a metal ion or a sugar, change their conformation, and can then bind with a channel protein to deliver that small molecule to the channel.
Think about steroid function, and you see the same thing.
Did I miss something here?
Posted by: U | May 10, 2007 7:56 PM
U,
The beauty is that auxin did not make the protein refold (he had structures +/- auxin), instead the real receptor for auxin was a cavity formed by the enzyme/substrate interface.
Some guy at ICCB who was disillusioned about how few small molecule inhibitors they got in their screens once explained that for a small molecule to inhibit the interactions of two large proteins, would be the equivalent of a football interfering with two football fields worth of interactions. It's hard. But perhaps a football can help two football fields interact, if one of the football fields has a mutation (or a pit) at a critical interaction site.
Posted by: apalazzo | May 11, 2007 9:06 AM
Hmm, I'd be wary about the statement of no refolding due to the +/- auxin structures. I guess I have to read the paper... and look at the temperature factors.
Posted by: U | May 11, 2007 9:08 PM
Still, no matter what, I'd have to say, I think it's great to see results like this on a system that is a standard experiment in high-school biology labs!
Posted by: U | May 11, 2007 9:10 PM