Function of mysterious disordered regions of proteins implicated in cancer revealed

Rohit Pappu and members of his lab were collaborators in the research

10.04.2023

Left to right, Rohit Pappu, Kiersten Ruff and Min Kyung Shinn

A close look at molecular grammar has led a multi-institutional research team, including engineers from McKelvey School of Engineering at Washington University in St. Louis, to reveal a key role for intrinsically disordered proteins known as intrinsically disordered regions (IDR) that are implicated in diseases ranging from cancer to neurodegenerative diseases.

Rohit Pappu, the Gene K. Beare Distinguished Professor in McKelvey Engineering, Kiersten Ruff, staff research scientist, and Min Kyung Shinn, a postdoctoral research associate, collaborated on the new research published Oct. 3 in Cell with Cigall Kadoch, associate professor of pediatric oncology at the Dana-Farber Cancer Institute and Harvard Medical School, and Clifford P. Brangwynne, professor of chemical and biological engineering at Princeton University.

Kadoch is a pioneer in the function and pathology of the cBAF protein complex. They approached Pappu, Ruff and Shinn, who work with molecular grammars of IDRs.

Previously, Pappu and Megan Cohan, who earned master’s and doctoral degrees in biomedical engineering from McKelvey Engineering in 2021, developed a method known as NARDINI, which Shinn optimized and Ruff combined into a robust pipeline now known as NARDINI+.

“Kiersten and Min Kyung, whom I refer to as our grammarians, deployed NARDINI+, and it became quickly apparent that the IDR of ARID1 has a distinctive grammar, one for encoding the driving forces for condensation, and the other, we reasoned, for imparting functionality,” Pappu said. “Dr. Kadoch and their student, Ajinkya Patil, worked with Kiersten and Min Kyung to design mutants that could unmask the encoded separability of functions.”

Pappu said the team also found that numerous cancer-causing mutations are localized to the ARID1-IDR, and Ruff's analysis shows that these mutations disrupt one or both of the functionalities mediated by the IDR.

“This work is unprecedented for the range of methods, the types of collaborations, the quality of insights, and the combination of both breadth and depth,” Pappu said. “Had Dr. Kadoch and Dr. Brangwynne been content with showing that condensates form and that this could be disrupted by deletion of the ARID1-IDR, we would not have been in a place where we knew that there must be separable functions. Had we not been drawn in by Dr. Brangwynne and Dr. Kadoch, and had the two impressive grammarians Kiersten and Min Kyung not brought their computationally derived evolutionary insights to bear and worked closely with the immensely talented Ajinkya Patil, we would not have been able to uncover the separability of functions encoded into the ARID1-IDR.”