Finding a tumor suppressor's groove

February 17, 2012
Figure 1: Crystal structure of the complex of the Arm domain of APC and Sam68. The groove on the Arm domain of APC contains highly conserved residues (magenta) that form numerous specific interactions with Sam68 residues (yellow). Credit: Ref. 1 © 2011 Elsevier Ltd

The tumor suppressor protein called adenomatous polyposis coli (APC) is a central genetic risk factor for colorectal cancer. In fact, mutations that potentially alter the structure or function of this protein are found in an estimated 85% of human colorectal tumors, which are currently the third highest-ranked cause of cancer-related death worldwide.

Unfortunately, APC is a very large protein with numerous interacting partners, making it a challenge to determine the direct impact of a given mutation. “The mechanisms by which these mutations lead to is still poorly understood,” says Shigeyuki Yokoyama, director of the RIKEN Systems and Structural Biology Center in Yokohama.

Structural analysis offers helpful insights into protein function, but obtaining these data can be difficult with such massive target proteins. Yokoyama and colleagues therefore decided to focus on one particular segment of APC, known as the armadillo repeat (Arm) domain. In particular, they were interested in understanding how Arm interacts with and inhibits Sam68, an APC-binding protein that is believed to contribute to the activation of genes involved with tumorigenesis.

The researchers determined that the Arm domain forms a helical structure, with an L-shaped groove for the recognition of binding partners. The Arm-interacting domain of Sam68, on the other hand, appears to be relatively disorganized until it binds this groove, an association stabilized by a number of interactions between specific amino acids on the two proteins (Fig. 1).  Yokoyama and colleagues were subsequently able to confirm the contributions of these residues by systematically introducing mutations and determining their impact on these proteins’ affinity for each other.

With this information in hand, the researchers assessed the potential significance of real-life mutations at these points of interaction. “We were able to map cancer-related APC mutations within this domain and analyze their effects on the structure of APC and on the binding of proteins to APC,” says Yokoyama. Indeed, some of the amino acid changes introduced by these appeared to be directly detrimental to complex formation between APC and Sam68.

Arm interacts with several other important proteins, and Yokoyama’s group plans to perform equally in-depth analyses to characterize the structural bases for these associations. However, he notes that the present findings—in conjunction with data obtained by co-author Tetsu Akiyama at the University of Tokyo—may already offer direct clinical utility. “We think that targeted disruption of the interaction between mutated APCs and Sam68 might be a good strategy to prevent the development of cancer,” says Yokoyama.

More information: Morishita, E.C., et al. Crystal structures of the armadillo repeat domain of adenomatous polyposis coli and its complex with the tyrosine-rich domain of Sam68. Structure 19, 1496–1508 (2011).

Related Stories

Recommended for you

Breast cancer researchers find bacteria imbalance link

October 19, 2017
Researchers in the United States have uncovered differences in the bacterial composition of breast tissue of healthy women versus those with breast cancer.

New study reveals breast cancer cells recycle their own ammonia waste as fuel

October 19, 2017
Breast cancer cells recycle ammonia, a waste byproduct of cell metabolism, and use it as a source of nitrogen to fuel tumor growth, report scientists from Harvard Medical School in the journal Science.

US regulators approve 2nd gene therapy for blood cancer

October 19, 2017
U.S. regulators on Wednesday approved a second gene therapy for a blood cancer, a one-time, custom-made treatment for aggressive lymphoma in adults.

New findings explain how UV rays trigger skin cancer

October 18, 2017
Melanoma, a cancer of skin pigment cells called melanocytes, will strike an estimated 87,110 people in the U.S. in 2017, according to the Centers for Disease Control and Prevention. A fraction of those melanomas come from ...

Drug yields high response rates for lung cancer patients with harsh mutation

October 18, 2017
A targeted therapy resurrected by the Moon Shots Program at The University of Texas MD Anderson Cancer Center has produced unprecedented response rates among patients with metastatic non-small cell lung cancer that carries ...

Possible new immune therapy target in lung cancer

October 18, 2017
A study from Bern University Hospital in collaboration with the University of Bern shows that so-called perivascular-like cells from lung tumors behave abnormally. They not only inadequately support vascular structures, but ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.