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Building a molecular machine: analysis of co-chaperones for assembly of ciliary dynein motor complexes

Principal investigator: Andrew JARMAN (University of Edinburgh)
Funding source: BBSRC
 Value: £428,356
 Start: 01-12-2018  /  End: 30-11-2021
Almost every cell of your body has a thin, hair-like outgrowth called a cilium. Some types of cilia are capable of bending or beating and are involved in fluid movement. Such 'motile cilia' are found for example on cells lining our airways for mucus movement as well as the fallopian tubes for wafting a new egg towards the uterus. Moreover, sperm cells swim by means of a beating flagellum, which is essentially a long motile cilium. All these cilia bend through the action of banks of 'motor proteins' within them. These motor proteins form huge molecular machines - some of the largest known in nature. Perhaps not surprisingly, assembling these motor protein machines is extremely complex and requires other dedicated proteins that act as 'molecular chaperones' to ensure they are built correctly during the construction of the cilium by the cell. This proposal concerns the identification of the chaperone proteins and analysing how they function in motor assembly.

The importance of motor assembly is illustrated by what happens when it goes wrong: primary ciliary dyskinesia (PCD) is a human inherited disease in which cilia are immotile due to failure of these motor proteins. The result of this is the patient has symptoms related to infertility and difficulties in clearing mucus, leading for instance to frequent and damaging chest infections. Severe cases also have situs inversus - in which internal organ positioning is disrupted (e.g. the heart is no longer on the left side of the chest). Mutations in many different genes cause PCD. Some mutations are in genes that code for the molecular chaperone proteins. How these chaperone proteins work is not clear. Moreover, the chaperone proteins are not unique to humans - the entire pathway of motor assembly is very ancient, and is found in organisms from protozoa (e.g. the swimming Paramecium) upwards. To further our knowledge of how motor proteins assemble, our strategy is to look in the fruit fly, Drosophila melanogaster. The fruit fly is easy to rear and to study. Sophisticated genetic and cellular approaches can be used in Drosophila to discover genes that are required for motor assembly. We shall examine the effect of disrupting the function of these genes. This is quite straightforward to achieve because in Drosophila, motile cilia are required only for senses and sperm, and so flies with defective motile cilia are easy to spot through obvious sensory deficits and male infertility. Moreover, recent advances in genetic and microscopy tools mean that we can develop much more sophisticated ways of probing the motor assembly pathway, within the context of a whole organism, than has been hitherto possible in animals.

Ease of gene discovery and analysis is not sufficient. Just as important is the fact that the molecular machinery of the cilium is completely conserved between insects and 'higher' animals. Therefore, the chaperone mechanisms discovered in Drosophila are likely to be important in animals and humans too. For studies into cilium biology it is cost-effective and ethically more acceptable to use Drosophila than more complex organisms where possible.