Birkbeck researchers determine the structure of a molecular motor
Work from Dr Anthony Roberts ’s laboratory in the Birkbeck/UCL Institute of Structural and Molecular Biology (ISMB), in collaboration with Dr Andrew Carter’s lab group at the MRC-LMB in Cambridge, has determined the structure of a motor protein that powers one of the cell's vital transport systems that is fundamental to human development.
To swim, move fluids and sense their environment, human cells (and those of many other organisms) construct long antenna-like organelles on their surface known as cilia. Defects in cilia are associated with a range of human developmental disorders. Many of these conditions can be traced to failures in a transportation system that moves building blocks and signalling molecules to and from the site of assembly at the ciliary tip.
The molecular motor, known as dynein-2, moves cargoes from the tips of cilia back to the cell body. To obtain sufficient quantities of human dynein-2 for this investigation, the researchers used recombinant technology to produce all of its constituent proteins in the laboratory. Using powerful cryo-electron microscopy (cryo-EM) instruments at Birkbeck and the UK national electron bio-imaging centre (eBIC), they determined the structure of dynein-2 to near-atomic resolution.
‘Seeing the 3D architecture of dynein-2 emerge from the data was exciting. It’s a testament to the power of cryo-EM that this technique could determine the structure of such a flexible and complex assembly,’ said lead author, Katerina Toropova.
The results shed new light on how transport within cilia operates. They reveal that dynein-2’s motor subunits are held together by an unusual number of extra proteins, which control the activity of the molecular motor and enable it to assemble with polymeric ‘trains’ that carry it to the tip of the cilium. Determining this structure is a step toward understanding the molecular basis of the diseases that arise from dynein-2 dysfunction, encompassing short-rib thoracic dysplasias with or without polydactyly, inherited disorders characterised by abnormal rib cage development with severe, often life-threatening, consequences.
Further Information
The research is published in Nature Structural & Molecular Biology.
The work was funded by the Wellcome Trust, Royal Society, BBSRC and MRC