Structural Biology and the Cell Cycle

Dr Victor M. Bolanos-Garcia

Research Activities

  • Functional and Structural Characterisation of Multiprotein Assemblies that Ensure Genome Stability
  • Health and drug discovery
 
Research Details
 
Maintenance of correct chromosome numbers is absolutely critical for all living organisms. An evolutionarily conserved and self-monitoring surveillance system, the spindle assembly for the mitotic checkpoint (SAC) has therefore emerged to ensure the timely and high fidelity transmission of the genetic material to an offspring. In humans, failure of the SAC is a major determinant of age-related genetic disorders, of aberrant chromosome segregation and genome instability and represents the leading cause of pregnancy loss, birth and development defects.
 
Recently considerable progress has been made in understanding the composition of the SAC and the recruitment hierarchy of its components. However, the molecular interactions of the SAC with the kinetochore have proved elusive, even though they are clearly indispensable for the accurate segregation of chromosomes. The understanding of the function and mode of regulation of this surveillance system requires definition of the structural details of the individual subunits and different subcomplexes. For this, we have exploited biochemical, biophysical, structural and cell biology methods including X-ray protein crystallography, NMR, small-angle X-ray scattering, surface plasmon resonance, analytical ultracentrifugation, isothermal calorimetry, ES-nanospray MS and yeast-two hybrid system. Highlights of our studies include crystal structures of functionally conserved N-terminal domains of Bub1, BubR1 and Mps1 (Fig. 1) and of BubR1 in complex with KNL1/Blinkin/Spc105. The structure of the complex revealed a novel KNL1/Blinkin/Spc105 binding motif (Fig. 2), thus providing the first molecular insights into the recognition mechanism underlying SAC signalling. The studies on the SAC and other signalling systems have shown that signalling assemblies often involve concerted folding and binding and cooperative interactions to give extended multiprotein assemblies. These have led to a general model for high signal-to-noise signalling involving weak binary interactions to well-defined but transient multiprotein assemblies. 
 
In summary, understanding how sister genomes are separated with high fidelity to opposite poles of the cell is a matter of great interest in Biology and Medicine. The research area has clear potential for application in diagnostic and treatment of birth and developmental defects, cancer and human aging-associated disorders, which have a great impact for the wellbeing and the Health and Biotechnology sectors. 

CONTACT US

Dr Victor M Bolanos-Garcia
vbolanos-garcia@brookes.ac.uk
+44 (0)1865 482778
Staff Profile