Project description
Decoding mechanisms of novel treatment for heart failure
Phosphorylation and dephosphorylation are the addition and removal of phosphate groups, carried out by kinases and phosphatases, respectively. Such processes are ubiquitously used by cells to modify the activity of proteins; these modifications are critical to many cell functions, among them cardiac signalling and calcium homeostasis. Deregulation of a specific protein phosphatase, PP1, is linked to cardiac pathologies. Scientists have recently developed peptides known as PP1-disrupting peptides or PDPs: they activate PP1 and have demonstrated therapeutic effects in the heart, but the mechanisms remain unclear. Given the many potential substrates of the phosphatase, identifying these mechanisms is challenging. With EU funding of the PDPcardio project, PDP developers are now working on novel methods to identify the scope of their actions, paving the way to specific and effective targeting of the phosphatase for cardiac therapies.
Objective
Protein phosphatase-1 (PP1) is a ubiquitously expressed enzyme known to dephosphorylate a large number of the phosphorylated serines and threonines. The catalytic subunit PP1c is bound to regulatory proteins in holoenzymes. These play specific and fundamental roles in physiological processes and pathologies. One key role lies in the regulation of important cardiac signaling pathways and calcium homoeostasis. Accordingly, deregulation of PP1 has been implicated in cardiac dysfunctions. Powerful tools to study PP1 biology are our own developed PP1-disrupting peptides (PDPs) that selectively release PP1c (bound to PDP: PDP–PP1c) activity in cells. Recently, we showed that PDP treatment counteracts kinase hyperactivity and seals the arrhythmogenic sarcoplasmic reticulum (SR)-calcium-leak in human heart failure tissue. Mechanistic data indicated that PDP–PP1c-mediated dephosphorylation of the ryanodine receptor type 2 (RyR2) is involved in this effect. Nevertheless, given the large amount of potential PP1 substrates, so far the scope of PDP action is unknown, and therefore the mechanisms underlying this beneficial and potentially therapeutic effect of the PDPs in heart failure are unclear and currently hard to investigate. PDPcardio will address these challenges by providing new chemical biology methodologies combined with proteomics approaches using PDPs to guide PP1c to its substrates and to identify PDP-mediated interactions of PP1. These strategies will enable identifying the scope of PDP action in general, and in particular they will be applied here in cardiomyocytes to study the effects of PDP–PP1c. The results will provide the basis to fine-tune targeting PP1 for the treatment of heart insufficiency. Furthermore, the principles and methods developed here will be applicable more generally for defining the interaction scope of target-bound ligands (drugs) as well as for using PP1 as tool in synthetic biology.
Fields of science
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomics
- natural sciencesbiological sciencessynthetic biology
- natural scienceschemical sciencesinorganic chemistryalkaline earth metals
- medical and health sciencesbasic medicinepathology
- medical and health sciencesclinical medicinecardiology
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
79098 Freiburg
Germany