Buddy-cops! Why evolution favours the odd couple

Inside our cells, the battle with viruses has a lot in common with 1980s action-comedy Lethal Weapon: both feature unlikely pairs of heroes. Each partnership  - virus-battling proteins and LA cops alike - has a reliable, straight-laced, by-the-book one and a loose canon, maverick one. 

Mel Gibson as loose canon Martin Riggs paired with Danny
Glover as straight-laced cop Roger Murtagh.
(Lethal Weapon, 1987)
In the cell, buddy-cop proteins police many of life's
important processes.

New research suggests that whether they're crime fighting or fighting an infection, the odd couple always gets the job done.

Life inside our cells may look very complex, but it's actually all a bit of a cheat. Evolution killed off what didn't work early on and copied what did work in massive amounts. Like 'buddy-cop' movies from the 1980s our cells are full of repeated bits, common sets of rules, re-used ideas. After all, why mess with a winning formula?

Research published recently in Nature Molecular Systems Biology has found a familiar pairing at the heart of several of life's processes: proteins which behave very differently, thrown together to protect and serve the cell.

Dr Alexander Ratushny and colleagues at the Seattle Biomedical Research Institute, USA, examined a duo of proteins called Interferon Regulatory Factors (IRFs), which defend  our cells against viruses. They found one of the proteins, IRF7,  responds to a viral threat in an all-or-nothing way, using positive feedback to boost its activity. Its partner protein, IRF3, is more sensitive, reacting to the developing situation by reigning in its partner when needed.

Tango and Cash (1989), a repeated buddy-cop formula.Turning
both partners into mavericks can have destructive results in
the cell, too.

Dr Ratushny's team identified similar partnerships in control of how our cells grow, balancing our cholesterol levels and at the heart of our early development.

The team used mathematical models (using algebra to simulate genes and proteins) to compare how well different combinations of proteins work together - asking which type of pairing could quickly respond to a threat, how sensitive they were to changes in the threat and, most crucially, how balanced the partnership was.

The model of the chalk-and-cheese, 'asymmetric' pair was the only one "predicted to be reliably controlled, which is critical for balanced yet rapid, antiviral and inflammatory responses".

Although the buddy-cop formula
is often repeated, not all examples
work as well as others.

So why have these buddy-cop proteins evolved? What makes them more favourable than, say, pairs of 'maverick' all-or-nothing proteins?

If you've seen the end of 'Tango and Cash' you'll know the answer already - a pair of loose canons can be very destructive. Similarly, when Dr Ratushny's team forced both members of a 'buddy-cop' protein duo to work under positive feedback (inside yeast cells), the results were overkill - their response was too strong. 

It appears that evolution used trial and error to find that the odd couple is the only way to get results.

Drug developers (not the kind found in Lethal Weapon) may now look for ways to trigger the wiring in our cells with an asymmetric pair at its core, such as the wiring connecting the liquorice root to diabetes.

There are also fresh ideas here for synthetic biologists looking to artificially coax a maverick protein into working with straight-laced partners inside our cells.

When they do, you may see a post here comparing their efforts to 1984 fish-out-of-water comedy "Beverly Hills Cop".

Reference:

Ratushny AV, Saleem RA, Sitko K, Ramsey SA, & Aitchison JD (2012). Asymmetric positive feedback loops reliably control biological responses. Molecular systems biology, 8 PMID: 22531117