by Matthew Cobb
The third of the Nobel science awards was announced this morning – it went to two US scientists, Robert J Lefkowitz and Brian K Kobilka, for their work on G-protein coupled receptors. For once, I actually understand some of the science involved. G-protein coupled receptors are a particular kind of cellular receptor that enable us to respond to a wide range of stimuli, including odours (which is why I understand this stuff). Lefkowitz (left) works at the Howard Hughes Medical Institute and Duke University, Durham, North Carolina, while Kobilka (right) now works at Stanford. Lefkowitz began work on the beta-adrenergic receptor in 1968 and Kobilka joined him in the 1980s; as the Nobel Citation puts it:
The studies by Lefkowitz and Kobilka are crucial for understanding how G-protein–coupled receptors function. Furthermore, in 2011, Kobilka achieved another break-through; he and his research team captured an image of the β-adrenergic receptor at the exact moment that it is activated by a hormone and sends a signal into the cell. This image is a molecular masterpiece – the result of decades of research.
The earliest receptors to have evolved will have worked by the stimulus (or ‘ligand’) directly opening or closing pores in the membranes of the earliest cells. This will have enabled single-celled organisms to migrate up chemical gradients in the primeval sea. Over evolutionary time, receptor mechanisms became much more complex, and many of the key receptors in your body involve a cascade of biochemical interactions, which begin when a receptor molecule (generally a snake-shaped molecule which wiggles in an out of the membrane) detects the stimulus. The change in the shape of the receptor molecule activates the associated ‘G-protein’, which is inside the cell and has three sub-units. Changes in the sub-units can then activate other proteins, enabling the cell to respond appropriately, by changing its internal environment, or, in the case of a neuron, by allowing ions to enter, thereby producing a neuronal response.
The amazing complexity of the G-protein coupled cascade – which no designer would ever build – shows the truth of Jacob’s aphorism that evolution doesn’t design, it ‘tinkers’. To give you some idea of what’s happening – all in the space of milliseconds – here’s a video:
Sweet (pun intended)! My Ph.D. thesis was on the calcitonin receptor. GPCRs are amazing molecules. The odor receptors are a great example of pseudogenes. Mouse OR genes are almost completely intact while two thirds of human OR genes have suffered fatal mutations.
“The amazing complexity of the G-protein coupled cascade – which no designer would ever build – shows the truth of Jacob’s aphorism that evolution doesn’t design, it ‘tinkers’. ”
Food for thought – the process of translation (decoding of mRNAs by ribosomes) makes extensive use of G-proteins and the core of the cycle that is in play with G-protein coupled receptors. Thus, in a sense, this tinkering involved the co-opting of activities that are fundamental to all life. (Assuming, of course, that ribosomes pre-date the receptors that are deservedly recognized with this year’s Nobel Prize.)
Very nice. It would only be enhanced by a demonstration of the speed of the reaction (as you note, milliseconds), and some sort of concrete example the downstream consequences of G-protein signalling.
Quite amazing how fast things happen in biochemistry.
I found this: http://www.nature.com/nature/focus/gpcrs/index.html which I’ll explore when I have a few spare hours.
You know, I’d appreciate that video a lot more if it didn’t simply jump to the conclusions, but instead answered Richard’s favorite question: “How do you know that?”
b&
Always a key question and the root of all learning.
Yes, and it’s one that is frustratingly absent from far too much of science education and science reporting.
The great thing about science isn’t the answers, but the repeatability. Who cares that apples fall at 10 m/s/s? What I want to know is, how do I figure out how fast apples fall?
(I did that experiment in high school, of course.)
That’s why the great part of Jerry’s book is the very first word of the title. Explaining what the conclusion of the science is well and good, but what good does it really do you to simply take those conclusions on faith?
b&
Any commentary on Faux News about the details as to why these gentlemen won the Nobel Prize in Chemistry?
That’s a rhetorical question of course. No one cares about science, at Faux News, unless it is something can create more gasoline.
Thanks Jerry for this. It is great to get some important biology explained (or at least overviewed) clearly. More of same, please
Interesting. I have had a keen interest in brain research and also am a complete geek about cellular processes so started to study these receptors. It is fascinating stuff.
Little complicated. Maybe meds will be able to be developed targeting these — but maybe not.
Most meds *do* target these receptors…
Oh oh! Evo-devo central dogma under question!
Isn’t science like the most fun thing ever. Just when you think you’ve got a decent model — blamo! — along comes another impersonal, non-lving physics thang to explain stuff. To wit:
Looks like phenotypes may be as much physics of cells vs. selection. Damn! Great fun!
from Science
Physico-Genetic Determinants in the Evolution of Development
Stuart A. Newman
Abstract
Animal bodies and the embryos that generate them exhibit an assortment of stereotypic morphological motifs that first appeared more than half a billion years ago. During development, cells arrange themselves into tissues with interior cavities and multiple layers with immiscible boundaries, containing patterned arrangements of cell types. These tissues go on to elongate, fold, segment, and form appendages. Their motifs are similar to the outcomes of physical processes generic to condensed, chemically excitable, viscoelastic materials, although the embryonic mechanisms that generate them are typically much more complex. I propose that the origins of animal development lay in the mobilization of physical organizational effects that resulted when certain gene products of single-celled ancestors came to operate on the spatial scale of multicellular aggregates.”
Nice podcast –
http://www.sciencemag.org/content/338/6104/217/suppl/DC1
I am all for everything being physics.