Structure and function of cilia and flagella - organelles that clear our lungs of pollutants
Cilia and flagella are tiny waving filaments with important functions in humans, such as clearing our airways. A 3D electron microscopy study of the normal (WT) and mutant varieties of flagella has revealed new details of the structure, protein composition, and connections between neighboring components formed by a crucial structural complex of this biological nanomachine, the "nexin-dynein regulatory complex" (N-DRC), which is shown in color on the left. In the poorly moving mutants, this structure is damaged or almost missing. This opens the way for building a new mechanical model of this device, and how it functions, along with mechanical testing of individual cilia and flagella, normal and mutant, in the Brandeis multi-mode optical microscopy laboratory.
Cilia and flagella are highly conserved sensing and motility organelles of eukaryotes and ciliary defects have been linked to many human diseases. The core structure of cilia and flagella, the axoneme, consists of a central microtubule pair and nine surrounding microtubule doublets that are connected by nexin links. Movement of cilia and flagella is generated by precisely orchestrated activity of many thousands of dynein motors. One of the key regulators of this activity is the dynein regulatory complex (DRC), but detailed structural information has been missing. By comparing the DRC structure of wild-type, 4 different drc-mutants and 1 drc-mutant rescue we were able to visualize the DRC in situ at molecular resolution, and to deconstruct a key complex in this biological nanomachine. This work has now been published (Heuser et al. 2009, JCB 187:921) Recently, the PIs Dogic, Fraden and Nicastro obtained outside funding from the W.M. Keck Foundation for studying "Active Matter", including the present seed project.
These images show lateral- and end-views of the basic structural element of the flagellum, including the long hollow microtubules and associated proteins, like motors and regulators. Normal structure of the N-DRC, a regulatory bridge (colored), at the left (WT), a mild mutant of the complex in the middle (sup-pf-4) and a mutant with more severe defects on the right (sup-pf-3). These images were obtained by cryo-electron tomography, revealing the 3D structure at the molecular scale.
|Brandeis MRSEC 0820492 seed cilia structure.ppt||612.5 KB|