The role of FAT-10 in tumor progression

 24 Feb 2015 Scientists in NUS collaboratively deciphered the molecular mechanism of FAT10-MAD2 interaction and demonstrated that its disruption inhibits tumor progression.

FAT10 (HLA-F-adjacent transcript 10) is commonly overexpressed in various tumors and its overexpression promotes tumor growth and malignancy, possible by interacting with the spindle checkpoint protein mitotic arrest-deficient 2 (MAD2). However, due to its insolubility, the underlying molecular mechanism remained unknown.

A team of biophysicists led by Prof SONG Jianxing from the Department of Biological Sciences in NUS delineated FAT10 structures of high dynamics, which did interact with MAD2. While a team of cancer biologists led by Prof LEE Caroline from the Department of Biochemistry in NUS revealed that mutation of the MAD2-binding residues inhibit tumor progression.

More specifically, ablation of FAT10–MAD2 interaction dramatically restricted the promalignant capacity of FAT10, which includes enhancing tumor growth in vivo, aneuploidy, proliferation, migration, invasion, and resistance to apoptosis in vitro.

Most importantly, the interface of FAT10 with MAD2 was demonstrated to be very specific and its disruption did not interfere with the interaction of FAT10 with its other known interacting partners. The interaction of FAT10 with MAD2 thus represents a key mechanism underlying the promalignant property of FAT10, and consequently its disruption may open up avenues for development of specific anticancer strategies. For example, molecules obtained from random screening or/and rational design capable of disrupting FAT10-MAD2 interaction might be further optimized to be anticancer drugs.

The success in delineating the NMR structures of “insoluble” FAT10 and its interaction with MAD2 highlights the importance of the discovery by Prof Song’s team that “insoluble” proteins could be solubilized in pure water (see Figure). In fact, his team also utilized the same approach to resolve the long-standing mystery of the TDP-43 N-terminal structure and Prof Philipp KAHLE from the University of Tübingen, Germany commented: “Song’s pure-water technique will reveal other structural siblings of ubiquitin.”

song 2

The image shows the NMR structure of the first ubiquitin-like domain of FAT10 (A), with five residues in spheres, which are important for binding to MAD2 (B). Mutation of the five residues would disrupt FAT10-MAD2 interaction which leads to inhibition of tumor progression. [Image credit: Song Jianxing]

 

References

1. Theng SS, Wang W, Mah WC, Chan C, Zhuo J, Gao Y, Qin H, Lim LZ, Chong SS, Song JX, Lee CG. Disruption of FAT10-MAD2 binding inhibits tumor progression. Proc Natl Acad Sci U S A. 111(2014) E5282.

2. Song J. Why do proteins aggregate? "Intrinsically insoluble proteins" and "dark mediators" revealed by studies on "insoluble proteins" solubilized in pure water. F1000Res. 2 (2013) 94.

3. Qin H, Lim LZ, Wei Y, Song JX. “TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA”. PNAS U S A. 111 (2014) 18619.