Chemistry, Biology and Physics in a single molecule: the story of PIP2
The difference between you and I, and a sponge, is cell signalling. Sponges—the sort that have lived on the sea bed for many millions of years—are masses of cells that are biologically indistinguishable. You and I are made of countless different sorts of cells that between them do all the different things required for us to be walking, talking human beings.
Like a large company, all those many different cells need to be marshalled so that they work together and thus function properly. It would be no good if all cells decided they wanted to be hepatocytes (liver cells), so they must communicate with one another to ensure that the right number do the right thing at the right time.
Inevitably, this is an immensely complicated process, and not one we fully understand. Even simpler-sounding processes like dealing with sugar, or moving our muscles requires several layers of communication, or signalling, between and within cells. It was this realisation that led scientists, particularly biochemists, to look for so-called signalling molecules. Once they started looking, they found them in abundance. The process is still going on today: last month a paper was published, providing evidence that a lipid previously thought to be essentially structural in nature, may have a signalling role .
Signalling molecules come in a variety of sorts. Some have very familiar names, like oestrogen and testosterone. Some dissolve in the cytosol (the the watery fluid inside a cell) and in the extracellular medium (the watery fluid outside cells), where others are based in a given location, like a membrane. The inositide lipids, a group that includes PIP2, are signalling molecules that are located in membranes. Their amphiphilic nature makes this inevitable initially, but there is a twist.
Part of how the PIP2 signal is made is elaboration of the water-soluble head group of the lipid. Processing of the PIP2 signal involves separating this head group from the fatty part, leaving a molecule called IP3 and a diglyceride (DAG). IP3 is water soluble and so diffuses into the cytosol, where it meets other membranes and releases calcium. This process is required for muscles to work. It also is involved in cell proliferation (growth and division), and when it goes wrong is responsible for well-known diseases such as Huntingdon’s chorea and Alzheimer’s disease. DAG’s functions as a signal are similarly broad. It activates a group of proteins called PKC. These proteins are responsible for ‘switching on’ other proteins. As you might imagine, the down-stream effects of this are several, including muscular activity, but also hormone secretion, and the production and metabolisation, of fats.
This understanding is the result of about 50 years’ work by biochemists. One might think that that would be enough, but scientists have other ideas. Interest from scientists who research the physical behaviour of lipids has prompted interest in the inositide family [2,3], which of course includes PIP2. Several biological studies have shown that PIP2 is present during important cellular events, such as the formation of vesicles  (part of the process of carrying nerve impulses) and during one called endocytosis [5,6,7], which is similar to what immune cells do to kill bacterial cells. Some evidence about the physical behaviour of inositides has already been published [2,3], much of which was surprising and so invites questions about what the others, like PIP2, do.
The chemistry of PIP2 is remarkable with respect to other lipids. Its large head group has complicated interactions with water and acids , that probably influence its physical behaviour and its molecular interactions with proteins, and thus its biological behaviour.
‘Probably’ is a very dangerous word in science, unfortunately. It frightens us scientists, making us want to reach for evidence and to run away from anyone who does not. Despite that, there is a solution. And it has a similarity with PIP2 itself. The answer is to research this molecule using more than one scientific discipline, together. So, like the PIP2 molecule with its several effects and influences, we need scientists who can do several different things.
This is not a new idea. In the nineteenth century, the science of ‘bio-chemistry’ was born, when it was realised that there was a good deal of chemistry in cells, and that understanding that chemistry was key to understanding how cells work. In the twentieth century, research questions such as the structure of DNA were solved by using physics and physical techniques. This is the basis for biophysics. Another form of this, medical biophysics, is useful for researching physical processes in disease. For example, the reason why the heart pumps blood is because of a change in pressure in the chambers of the heart. When that goes wrong, it is a physical process as well as a biological one, and often, so is the solution.
So, how does this fit with PIP2? The multi-disciplinary work that is tackling that problem is called chemical biology. This term refers to the use of chemical and physical techniques to solve research questions in biological systems. This means it includes using LASERs to treat arthritis, computers to model protein behaviour, but also x-rays to work out what lipids do. This sounds very general, and it is. Focus is important in science, but in chemical biology the focus is on the problem, rather than how it is solved. The point is to identify the question and then use whatever techniques, from whichever discipline, are required to answer it thoroughly. This is what holds the key to weaving the disparate threads of PIP2, of arthritis, of protein behaviour and all sorts of other things, into a coherent understanding.
 S. Liu, J. D. Brown, K. J. Stanya, E. Homan, M. Leidl, K. Inouye, P. Bhargava, M. R. Gangl, L. Dai, B. Hatano, G. S. Hotamisligil, A. Saghatelian, J. Plutzky, C. H. Lee, Nature, 2013, 502, 550. DOI: 10.1038/nature12710
 S. Furse, N. J. Brooks, A. M. Seddon, Rudiger Woscholski, R. H. Templer, E. W. Tate, P. R. J. Gaffney and O. Ces, Soft matter, 2012, 8, 3090-3093. doi: 10.1039/c2sm07358g
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 I. Milosevic, S. Giovedi, X. Lou, A. Raimondi, C. Collesi, H. Shen, S. Paradise, E. O’Toole, S. Ferguson, O. Cremona and P. De Camilli, Neuron, 2011, 72, 587-601.
 R. Zoncu, R. M. Perera, R. Sebastian, F. Nakatsu, H. Chen, T. Balla, G. Ayala, D. Toomre and P. V. De Camilli, Proceedings of the National Academy of Sciences, 2007, 104, 3793-3798.
 G. Di Paolo and P. De Camilli, Nature, 2006, 443, 651-657.
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 E. E. Kooijman, K. E. King, M. Gangoda, A. Gericke; Ionization Properties of Phosphatidylinositol Polyphosphates in Mixed Model Membranes, Biochemistry, 2009, 48, 9360-9371.
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[…] This exciting increase in the understanding of sphingolipids, from a variety of research fields, remains strong. Some very recent research provides evidence that sphingolipids have a role in the physical process of division in at least one type of mammalian cell . This physical role of this class of lipids is an unexpected contrast to the biological role sphingolipids have as molecular messengers in processes such as angiogenesis, neurodegeneration and diabetes. However it may not be unique; it appears that inositide lipids have both structural and biological roles. […]
[…] The two papers offer a tantalising picture of what may occur through the whole control mechanism. Yamaga et al. report that removing a protein called PLC, that metabolises a signalling lipid, increases exocytosis . In other words, the substrate for PLC increases exocytosis. The substrate is an old friend of this blog, PIP2. […]
[…] of S. cerevisiae with a mutation of its inp51 gene have shown that a major signalling lipid called PIP2 [link] is linked to both membrane fluidity and cell growth. This suggests that membrane fluidity is […]