Fibrillin puzzle a step closer to completion
Professor Penny Handford and colleagues in the Biochemistry Department have revealed for the first time the structure of part of the fibrillin protein, helping to build up a more complete picture of how this protein is packed in the extracellular cushioning around our cells. The findings are published in a recent paper in Structure1.
'It's a good example of how having structural biology in the department can help people like us working on different biological targets.'
Their work will also lead to a better understanding of how mutations in fibrillin cause Marfan syndrome, a connective tissue disorder that affects around 1 in 5000 people.
Fibrillin is a huge protein that forms the structural backbone of microfibrils, an essential extracellular component of many different tissues. Microfibrils confer elasticity to some tissues whilst in others, such as the eye, they have an anchoring function and provide the tissue with tensile strength.
Human fibroblast cells adhering to fibrillin
More recently, scientists have found that microfibrils are an important and readily-available source of growth factors which stimulate cell growth and division.
Professor Handford's group is interested in linking the function of the protein to its structure. 'There is the biomechanical property, but there's also a regulatory function which is emerging, which is another reason why it's important to know the structure of microfibrils,' she explains. She collaborates with members of the department's X-ray crystallography and Nuclear Magnetic Resonance (NMR) facility to study this.
The structure of very large molecules like fibrillin can be frustratingly difficult to solve. Rather than tackle the structure of the full-length protein, scientists resort to studying more manageable bite-sized, structurally-distinct pieces known as 'domains'. The domains retain their original structure, allowing scientists to piece together the overall structure.
A diagramatic representation of the fibrillin molecule expanded to show the structures of some of the domains that Professor Handford's group has solved.
Using this domain-specific approach, Professor Handford's group has determined all the structures to date in the fibrillin protein. The group has now solved the structure of an additional domain called the hybrid domain using X-ray crystallography.
The domains are found in slightly different forms along the length of the fibrillin molecule, making it easier to build up a model of the protein's overall structure. 'Because of the homology we can model pretty much the bulk of the protein, probably 75%,' explains Dr Sacha Jensen, the senior postdoctoral researcher who worked on the paper.
Their work indicates that the majority of the fibrillin molecule is near linear in shape. It also backs up other studies which suggest that the fibrillin molecules lie in a stretched out fashion in the microfibril.
a) Rotary-shadowed electron microscopy image of isolated microfibrils, b) The two main models currently proposed to explain the organisation of fibrillin within the microfibrils: a folded back or extended structure.
Professor Handford points out that the work would not have progressed so smoothly without the help of departmental colleagues, in particular, Dr Edward Lowe the X-ray Facilities Manager. 'It's a good example of how having structural biology in the department can help people like us working on different biological targets. We have really been able to progress in the field because of the proximity of the world-class facilities here.'
Dr Jensen, who worked closely with Dr Lowe on the project, agrees. 'It's been a huge help to be able to do this here.'
A crucial sticking point in their research is the structure of the unique domains at the ends of the molecule. This has turned out to be a particularly challenging task – having exhausted the possibility of using X-ray crystallography, the group is optimistic that NMR will prove successful.
1. Jensen, S. A., Iqbal, S., Lowe, E. D., Redfield, C., and Handford, P. A. Structure and Interdomain Interactions of a Hybrid Domain: A Disuphide-Rich Module of the Fibrillin/LTBP Superfamily of Matrix Proteins'. Structure 17, 759-768 (2009).