The shape of things to come: control of new blood vessel growth
Inforzato, A., Baldock, C., Jowitt, T.A., Holmes, D.F., Lindstedt, R., Marcellini, M., Rivieccio, V., Briggs, D.C., Kadler, K.E., Verdoliva, A., Bottazzi, B., Mantovani, A., Salvatori, Day, A.J. The angiogenic inhibitor long pentraxin PTX3 forms an asymmetric octamer with two binding sites for FGF2. (2010) J. Biol. Chem. 285, 17681-17692.pubmed
The growth of new blood vessels a process termed angiogenesis occurs during cancer (providing a blood supply to the tumour), and can also contribute to tissue damage in diseases such as arthritis and age related macular degeneration (AMD). Therefore, in recent years new drugs that block angiogenesis have been developed as treatments for certain cancers and for AMD (a major cause of blindness). This paper is focused on a human protein called pentraxin-3 (or PTX3 for short), which is made by the body during inflammation, and is a naturally occurring inhibitor of new blood vessel formation. It is already known that PTX3 can bind with another protein (termed FGF2), a so-called “growth factor” that promotes angiogenesis. However, this interaction, which blocks the function of FGF2, was poorly understood because the shape of the PTX3 protein was not known.
Here we have used sophisticated techniques (including information derived from light and X-ray scattering) to reveal the shape of the PTX3 protein. This has allowed us to determine that 8 identical PTX3 protein chains assemble into a single PTX3 molecule, which has an elongated shape with two differently sized “domains” connected by a short stalk (see figure 1). We have also been able to predict how the eight chains are arranged relative to one another – that is, how they might fit together to form this unusual, and asymmetric, shape. In other experiments, we have found to our surprise that only two FGF2 molecules bind onto each molecule of PTX3 (which was less than expected). However, this can be explained on the basis of the shape and arrangement of the PTX3 protein. This shape information also helps us to make predictions as to how PTX3 may be working in the context of the immune system and in its critical role in ovulation. Therefore, this study has provided exciting new insights into the PTX3 protein, explaining its overall shape and how this allows it to block angiogenesis. It has also facilitated further investigations that will build on this research, where we hope we can use what we have learnt to help develop new treatments for a range of diseases, for example, involving unwanted blood vessel formation.
Simon Foulcer and Tony Day.