GPCR

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China’s Great Proletarian Cultural Revolution was launched on May 16, 1966 (next year will be the 50th anniversary!) 

Workers World Party founder Sam Marcy wrote groundbreaking Marxist anlaysis of the GPCR as it was unfolding, drawing on the experience of the French and Soviet Revolutions. Here is one of his most important pieces:

“Mao didn’t wait for Thermidor” from the book China: The Struggle Within

GPCR-G-protein interaction theory

The crystal structure of the beta2-adrenergic receptor coupled to the Gs G-protein was published on Nature (online) couple of months back and now it has made it to the cover of last week’s Nature (Magazine). Apart from the fact that it might be “the” study that provides crucial insights into the functioning of the ever-present GPCRs, the volume and quality of work that went into this study is just mind-boggling. The way they vanquish every obstacle that they face along the way using some ingenious techniques is worth appreciating. As Dr. Thue W. Schwartz points out in the introductory/review article -

A complete  review of the biochemical methods used to prepare the material that eventually yielded crystals for Rasmussen and co-workers’ study would occupy an entire semester-long course in graduate school (and maybe it should).

 

But another article that was also published in the same week which I found to be more interesting (if at all possible) was - Conformational changes in the G protein Gs induced by the beta2-adrenergic receptor. They use the peptide amide hydrogen deuterium exchange mas spectroscopy (DXMS) to understand the dynamic changes that occur during receptor-G protein binding and the subsequent GDP-GTP exchange. The basic concept is that the positions of the complex that shows most Hydrogen-Deuterium exchange, are considered to the most dynamic and therefore considered as vital conformational changes required for G-protein activation. The main conclusions from the study were -

  • The C-terminus of Gα subunit penetrates into the cytoplasmic core of the agonist-bound receptor.
  • The N-terminal of Gα subunit interacts with the second intracellular loop (ICL 2) and connects the receptor to the P-loop (which holds the nucleotide) through the β1-strand. 
  • The β1-strand conformational change disrupts a hydrogen bond network and causes changes in the P-loop holding the GDP. This interaction results in the GDP release.
  • The further hypothesis is that this hydrogen bond disruption also leads to an open (and empty) conformation of the Gα and thus allowing the entry of GTP and the activation of the G protein.

The remarkable number GPCR studies published over the past few months from Dr. Kobilka’s lab deserve a standing ovation. Each of these studies sheds a new light on the working of (one of) nature’s unique and therapeutically vital receptor and I can’t wait for their next paper.

“In recent days, news of the passing of Li Junxu (李君旭) has been little more than a whisper, muffled amid the story of the crackdown on Dongguan’s sex trade. But 38 years ago, Li Junxu was the centre of a great big news story when it was reported that the 23 year-old factory worker had been arrested for fabricating a text called “The Last Will and Testament of the Premier” (总理遗言).

The world of Chinese politics is a black box, and black-box politics naturally gives rise to “rumour.” I remember very clearly the end of the Cultural Revolution, how people would whisper things privately and pass on speculative information. The core of most of this speculation was Jiang Qing, Mao Zedong’s last wife. In 1976, Deng Xiaoping was criticized in the movement to “strike back against the right-deviationist wind.” In the midst of this, Zhou Enlai passed away and this drove an undercurrent of rumour and speculation.”

For the full account, see Qian Gang’s “Who is Li Junxu” at China Media Project (17 Feb 2014)

Image: Li Junxu. From Yuan Minzhu, Reassessing the ‘Premier’s Will Case’ of 1976 That I Experienced

It was the mid-1970s,” reminisces a Chinese blogger, writing over three decades later in November 2009. “I was in my third year of primary school … in a small Jiangsu town. One afternoon, the teachers called the students of the neighbouring class to join ours —those who couldn’t fit ended up being sat in rows in the corridor — and we immediately thought oh, another rehearsal for our observed classes. Strangely, it actually turned out to be a music lesson. The teachers carefully moved the school organ into our classroom, the principal and the head supervisor seated themselves next to it, and then our star teacher, Teacher Shen, began to teach us a song. The novelty of the whole set-up made all of us children pretty excited. The song was called Let’s Make Antonioni Mad (《气死安东尼奥尼》).

“Now, my grandfather is aging. His foes are either aging or dead, and they talk to each other very little. Lei Enzhan, the “rightist” teacher, once said that he didn’t care who treated him badly four decades ago. But my grandfather still feels much regret. In fact, he wants to say sorry to Lei Enzhan.”

For more, see Shawn Lei, “My Grandfather the Red Guard,” at Tea Leaf Nation (25 June 2013) 

Image: Wikimedia Commons

Hothouse flowers cannot stand wind and weather, they lack vitality. Real proletarian revolutionary fighters ought to face the world and brave the storm, the great world of mass struggle and the mighty storm of mass struggle. The successors to the proletarian revolutionary cause can grow up healthy only in mass struggles and in the great storms and waves of revolution. The mighty storms and waves of the revolutionary mass movement are a tremendous force that mobilizes, educates and remoulds people.
—  “Renmin Ribao” (People’s Daily) editorial, July 26, 1966. Quoted from “Peking Review” #31
Now consider for a moment, just for a moment, that you are a G-protein-coupled receptor, okay. Are you considering that? Which one are you? No, don’t tell me. It’s too personal. Okay, so in comes an agonist and you’re activated and you’re kickin’ out that GTP and doing what you have to do, you feel good. You feel great, life is good. But the freaking agonist doesn’t go away. It’s pouring it on, pouring it on, and after a while you get tired and you say “Man, I have to stop this whole freaking G-protein-activating thing.” So, there is a mechanism to turn it off, and this is called desensitization.
—  One of my lecturers, doing the best job of explaining GPCRs
WTF are GPCRs?: Signal Transduction and Messaging Pathways (part three: GPCRs and CREB)

We’ve met other receptors, but now, let’s revisit GPCRs.

Signal molecule attaches to the receptor, which activates the G protein.

G proteins have 3 subunits and the alpha subunit usually is attached to GDP, but then swaps it out for guanine triphosphate when activated.

The alpha subunit activates cyclase. What happens next is the cyclase takes two phosphates from ATP and creates cyclic AMP (one phosphate). Image following is not mine, and also is not particularly needed, but it kind of shows where the phosphates are located.

The AMP activates the protein kinase A, which causes the PKA to detach from its subunit. The now-activated PKA passes through a pore in the nuclear envelope and phosphorylates CREB (cAMP response element-binding protein) because that’s what kinases do. The activated CREB binds to the part of the DNA that is the CREB-binding element and the CREB-binding protein (CBP) binds to CREB, which starts transcription. This allows CREB to turn certain genes on/off - it’s a transcription factor.

Wikipedia is surprisingly helpful.

Supporters of Mao Zedong raise the “Little Red Book” in a Beijing stadium in 1967. Officially titled Quotations from Chairman Mao Zedong, the book is a collection of speeches and writings on a wide range of subjects related to socialist thought. It was considered a symbol of the Great Proletarian Cultural Revolution and is among the most printed books of all time.

Read the Red Book here