Director of the Department

Photo: Peter Barta © BMC/STJUDE

Brenda Schulman

Photo: Peter Barta © BMC/STJUDE

How are timing, location, and activities of proteins controlled?

Research Department "Molecular Machines and Signaling" (Brenda Schulman)

<p>APC/C, a molecular machine, forms numerous transient assemblies to orchestrate cell division. The cryo electron microscopy structures show dynamics between 1) a “closed” complex with MCC that restrains APC/C<sup>CDC20</sup> when chromosomes are not properly oriented on the mitotic spindle, 2) an “open” complex with MCC that is ubiquitylated as a prelude to cell division, and 3) a complex with substrate and the E2 UBCH10 that marks substrates for degradation and promotes mitosis.</p> Zoom Image

APC/C, a molecular machine, forms numerous transient assemblies to orchestrate cell division. The cryo electron microscopy structures show dynamics between 1) a “closed” complex with MCC that restrains APC/CCDC20 when chromosomes are not properly oriented on the mitotic spindle, 2) an “open” complex with MCC that is ubiquitylated as a prelude to cell division, and 3) a complex with substrate and the E2 UBCH10 that marks substrates for degradation and promotes mitosis.

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A major form of regulation involves protein and membrane remodelling by their linkage to the small protein ubiquitin, or to structurally-related ubiquitin-like proteins (UBLs).  Ubiquitin and UBLs control timing, subcellular location, assembly, conformation, and activity of thousands of different human proteins and macromolecules.  Moreover, defects in ubiquitin and UBL pathways are associated with numerous diseases including cancers, neurodegenerative disorders, and viral infections.  The group of Brenda Schulman investigates how this regulation is achieved by conformationally dynamic, multiprotein assemblies called “molecular machines”.

Schulman’s group has shown that flexible molecular machines are transiently harnessed into specific conformations by different regulatory factors, which specify distinct activities.  Recent work on one such molecular machine, the Anaphase-promoting complex/Cyclosome, or “APC/C”, which is a master regulator of cell division, is shown in the movie.  Schulman’s team, along with collaborators Jan-Michael Peters (IMP, Vienna) and Holger Stark (MPI Biophysical Chemistry, Göttingen), used cryo electron microscopy and other methods to visualize the different assemblies formed by APC/C and its collaborating activators, inhibitors, substrates, and E2 enzymes to regulate ubiquitylation and faithfully orchestrate the sequential steps in cell division.

 
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