Tuesday, 29 November 2011

Structural Secrets of an Ancient Viral Plague

Research in Biological Sciences at Birkbeck, and several related departments at neighbouring University College London, is combined into the Institute of Structural Molecular Biology. The Institute holds a regular seminar programme - every Wednesday lunchtime during termtime - in which it invites excellent scientists, many with links to the colleges, to present their research. A few weeks ago, the seminar speaker was an electron microscopist, Sarah Butcher, who is based at the University of Helsinki in Finland. Her group has been investigating the structure of a virus that causes a very well-known disease: measles.

Measles has been known of for millennia. The disease (although of course not its cause) was first described in ancient Egypt. It is one of the most infectious viruses known, but people who encounter measles (if at all) as an unpleasant childhood affliction are often surprised to learn that it is a killer. About 164,000 people lost their lives as a result of measles infection in 2008, most from lingering immunosuppression rather than the acute infection. Most deaths occur in Africa and south Asia; a smaller epidemics have recently arisen in the UK when the MMR vaccination lost popularity over the MMR autism scare.

The measles virus is a paramyxovirus; an enveloped virus with a single strand of RNA as its genome, and closely related to the viruses that cause mumps, respiratory syncytial virus (RSV) infection and para-influenza in infants and children. It has two surface proteins and iis thought to attach directly to the membranes of the cells it infects via one of these.

Until recently, structural studies of the measles virus have been fairly limited. Many groups have studied it using an electron microscopy technique called negative staining, but that can only see the virus' surface. Structures of one intact measles virus protein and domains of three others have been deposited in the Protein Data Bank; the haemagglutinin (e.g. PDB code 2RKC); two separate domains of the phosphoprotein (1OKS and 2K9D) and a structure of fragments of two proteins simply called P and N bound together (1T60).

Sarah Butcher and her group used a technique called cryo-electron microscopy, which allows the interior of viruses to be visualised, to study the measles virus. Their results led them to focus on the matrix protein, which is thought to be important for the assemby of the virus (the protein coloured cyan in the images below). All previous models had placed the matrix protein covering the inner part of the viral membrane. What the Butcher group saw, however, was completely different. They could see a protein surrounding parts of nucleocapsid - the viral RNA and its associated, protective protein - and further analysis identified this as the matrix protein. The matrix binds tightly to parts of the nucleocapsid to make rod-like structures, and these fold into anti-parallel units that are somewhat remniscent of antiparallel beta sheets in proteins. This model suggests that the process of virus replication will be more complex and yield more potential drug targets than has previously been thought.
Two models for the organisation of proteins and RNA in the measles virus. Top: the old model, with the matrix protein (cyan) surrounding the virus coat. Bottom: the Butcher group model, with the matrix protein surrounding parts of the nucleocapsid. Figure credit: Proc. Nat. Acad. Sci. USA (2011)

Structures of proteins from other viruses, particularly HIV and influenza, will be covered quite extensively later in the PPS course. We don't study the technique used in this study, cryo-electron microscopy, in PPS but it is covered in one of the options for the second year of the PPS course, Techniques in Structural Molecular Biolog