Structure of key protein for cell division puzzles researchers

Human cell division involves hundreds of proteins in its nucleus. Knowing the 3D structure of these proteins is crucial to understanding how our genetic material is duplicated and passed down through generations. The groups of Andrea Musacchio and Stefan Raunser at the Max Planck Institute of Molecular Physiology in Dortmund can now reveal the first detailed structure of a key protein complex for human cell division known as CCAN. Using cryoelectron microscopy, the researchers demonstrate important properties of the complex’s 16 components and challenge previous assumptions about how the complex can recognize the centromere, a crucial region of the chromosomes in cell division.

At the center of cell division

The centromere is a narrowing of the chromosome, made up of DNA and proteins. Most importantly, the centromere is the kinetochore doll, a machinery of about 100 proteins that drives the separation of two identical chromosomes during cell division and their delivery to the daughter cells. Previous research has shown that kinetocorns dock on the centromere through the CCAN complex: CCAN interacts with centromere protein A, the centromere’s landmark protein. CCAN is also responsible for replenishing the centromere protein A when cell division has taken place. Nevertheless, the details of the interaction between CCAN and centromere protein A remain elusive. “Understanding how CCAN recognizes and binds to the centromere can potentially lead us to build a centromere from scratch,” says Musacchio. The centromere is a major obstacle for synthetic biologists who aim to construct artificial chromosomes to restore missing functions or introduce new ones into cells.

Basically unresolved issues

Researchers identified the CCAN complex over 15 years ago. “Still, building a pipeline to synthesize all proteins in vitro has been a major obstacle,” says Musacchio. After receiving an initial reconstitution of the human CCAN complex in vitro, Musacchio teamed up with Stefan Raunser, also at MPI Dortmund, who applied cryoelectron microscopy to the entire CCAN protein complex.

In the new publication, the MPI groups have been able to determine the 3D structural details of the human CCAN complex, highlighting its unique properties and the implications for an interaction with the centromere protein A. “Contrary to what was expected, this structure does not directly recognize the centromere protein A in the standard configuration, “says Musacchio. Centromer protein A is usually packed with DNA and other proteins as a nucleosome, the standard unit of genetic material. The authors now suggest that the centromere protein A may be embedded in the centromere with a different configuration that may facilitate the crucial interaction with the CCAN. They plan to identify conditions that could lead to this new configuration and prove their hypothesis.

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