Revealing the motile machinery of spermatozoa by in situ structural biology

The lack of biological insight into human spermatogenesis and general sperm biology are limiting factors for the development of a male contraceptive.

In situ structural biology has now come of age, and fantastic work in ciliary model organisms show how it can be used to identify all proteins of the motile apparatus as well as their interactions.The overall aim of this proposal is to provide a zoomable map of the human sperm tail 3D structure using a combination of electron tomography (ET) and single particle analysis (SPA).

Such a map would reveal structural differences along the sperm tail as well as detailed structural/functional information how the beat is created and regulated.

Applying structural biology to the inside of human spermatozoa we have already identified a new helical complex inside microtubules (TAILS), and identified its two protein components, both of which had been implicated with male infertility.

Here, we will now investigate the role of TAILS inside sperm tail microtubules structurally, using SPA, and functionally, using TIRF microscopy.Revealing the fine details of the entire human sperm tail structure will provide new insights into human sperm biology and male (in)fertility.

In situ structural biology of the motile machinery will also reveal protein-protein interactions which could be disturbed to stop sperm motility: potential future drug targets for a male contraceptive.