01 October 2019

New insights into substrate selection for an essential protein phosphatase

PP4 is a nuclear serine and threonine protein phosphatase known to regulate numerous essential cellular processes but so far, it has not been known how PP4 recognizes the proteins that it dephosphorylates. The new study reveals how PP4 selects its substrates and brings researchers closer to understanding how PP4 controls signaling in a broad range of nuclear processes, such as the 3 dimensional shaping of chromatin and processing of RNA.

Multi-disciplinary effort
The project has been a multi-disciplinary effort that included the Montoya group at CPR, who performed x-ray crystallography studies of PP4 subunits interacting with peptide models of protein substrates. Researchers from Norris Cotton Cancer Center (US), Institute of Cancer Research (UK), and Uppsala University (Sweden) also contributed.

Model of a subdomain of the PP4 protein phosphatase (PP4 domain) interacting with a peptide (PP4-binding peptide) containing the PP4 binding motif that the researchers have identified in the new study.

Having identified the binding specificity of PP4, the researchers performed a systems-wide proteomic analysis of PP4 interacting proteins and were able to identify the PP4 binding motif in a wide range of proteins that control essential nuclear processes. These results provide an overview of potential PP4 substrates, which improves our understanding of known PP4-regulated signaling pathways and uncovers novel PP4-regulated pathways.

The structural information uncovered in the new study has promising perspectives for development of novel drugs targeting PP4. “Our studies indicate that PP4 binding specificity is very selective, which means there is a good chance of finding specific small molecule inhibitors of PP4. This is very interesting in a clinical perspective, since inhibition of PP4 is a potential treatment strategy for certain cancers, as recently shown by clinical proteomic studies from the Mann lab at CPR” says Professor Jakob Nilsson.

The study A Consensus Binding Motif for the PP4 Protein Phosphatase is published today in Molecular Cell.

Read more about the Nilsson Group here.

Contact points
Professor Jakob Nilsson
Telephone: (+45) 35 32 50 53
E-mail: jakob.nilsson@cpr.ku.dk