Intrinsic and extrinsic regulation of the anaphase-promoting complex
By: by Sashank Kurapati Reddy
Published: 2007
Language: eng
Number of pages: 145
Description: Orderly progression through the cell cycle is governed by the timely activation and inactivation of key regulatory proteins, such as cyclin-dependent kinases. The anaphase-promoting complex (APC) plays a critical role in inactivating these regulators by promoting their ubiquitin-dependent proteolysis. APC substrates are degraded in a sequential fashion, ensuring that the cell cycle events governed by these substrates occur at the proper times. The mechanism by which APC achieves this temporally ordered destruction of substrates is not known. We show herein that substrate ordering reflects the processivity of multiubiquitination by APC and is achieved by mechanisms intrinsic to APC and its substrates. Processive substrates acquire full-length ubiquitin chains in a single round of APC-binding and are consequently degraded earlier by the proteasome. By contrast, distributive substrates require multiple rounds of APC-interaction to achieve multiubiquitination, rendering their ubiquitination susceptible to competition by more processive substrates or reversal by deubiquitinating enzymes (DUBs). The mechanism we describe suggests that the ordered proteolysis of APC substrates can be accomplished by intrinsic interactions between APC and substrates alone.

Superimposed on this intrinsic regulation are a host of extrinsic controls that link APC activity to intracellular conditions. A critical extrinsic control is provided by proteins of the spindle checkpoint, which restrain APC activity in early mitosis until all kinetochores achieve bipolar attachments to the mitotic spindle. Unattached kinetochores promote the binding of checkpoint proteins Mad2 and BubR1 to the APC-activator Cdc20, rendering it unable to activate APC. Once all kinetochores are properly attached, however, cells inactivate the checkpoint within minutes, allowing for the rapid and synchronous segregation of chromosomes. How cells switch from strong APC-inhibition prior to kinetochore attachment to rapid APC-activation once attachment is complete remains mysterious. We find that checkpoint inactivation is an energy-consuming process involving APC-dependent multiubiquitination. Multiubiquitination by APC leads to the dissociation of Mad2 and BubR1 from Cdc20, a process that is reversed by a Cdc20-directed deubiquitinating enzyme. The mutual regulation between checkpoint proteins and APC couples accurate segregation of the genome to timely mitotic progression.
Notes: "May 2007."

Thesis (Ph.D., Dept. of Biophysics)--Harvard University, 2007.

Includes bibliographical references.