Primary microcephaly is a hereditary disease characterised by reduced brain size from birth and mental retardation. It occurs in ~1 in 10,000 individuals in some populations, but, importantly, it is one of few diseases where we can directly trace the effects of single mutations to brain development and cognitive functions. As a result primary microcephaly cases have proved instructive in identifying crucial brain development factors for which no backup systems exist. Centrosomes, are small organelles in human cells that organise a network of thin filaments (known as microtubules) that are essential for cells to grow, duplicate, move and sense their surroundings. Defects in centrosomes have been implicated in microcephaly. Five out of nine genes known to cause the disease correspond to centrosome components, and these include three proteins known to be essential for the formation of these organelles. In addition to microcephaly, centrosomal defects are causative agents for multiple human medical conditions, including male sterility, ciliopathies and possibly cancer. Thus, understanding how centrosomes form is an important biological question with direct medical relevance. Over the last few years our group, and others, have shown how a single protein, SAS-6, forms the initial framework onto which centrosomes are build. Crucial to this understanding was a combination of biophysical, structural and cell biology tools that allowed us to analyse the shape of essential proteins, envision how such proteins might join to form molecular machines, and test these insights in human cells. Here, we propose to build upon our understanding of the initial centrosomal framework by studying three protein components (Cep135, CPAP and STIL) that link to it. We have selected these components because they are essential for centrosomes, they appear to be connected to one another and to SAS-6, and importantly, they are all directly implicated in primary microcephaly. We believe that understanding the role of these three proteins will also inform us on how centrosomes are formed in normal cells and how defects in them cause severe diseases. We expect that these results will underpin future efforts on how to treat such diseases. Our group has long experience in the biophysical and structural biology methods necessary for the pursuit of this project. However, we do not rely on our core competencies alone. Our goal of understanding the centrosome structure is shared with internationally acclaimed groups in Oxford and abroad, with whom we collaborate. Our network of laboratories provides the broadest possible base of technical expertise and, thus, the best hope for determining how centrosomes form.