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5 great reads: Protein-protein interactions and disease

Proteins rarely act alone, in fact, it has been shown that over 80% of proteins perform their functions in groups.

These protein-protein interactions are essential for many cellular processes and are implicated in a variety of inherited, somatic and pathogenic diseases. As a result, considerable research is now focused on the identification of protein binding partners, their modes of action and the potential to disrupt their interactions.

Here are five of our favorite recent publications, highlighting both the role of protein-protein interactions in disease and how the characterization of these interactions may allow the development of new therapeutic strategies.

Harnessing the host response to Ebola infection


Although first identified in 1976, in a village near the Ebola River in the Democratic Republic of Congo, the Ebola virus only really entered public consciousness in 2013, when the largest ever outbreak occurred in West Africa. This three-year epidemic, resulted in 28,616 suspected cases and 11,310 deaths.

There are currently no effective medical treatments for Ebola and scientists around the world are studying the virus to identify potential drug targets. In one such effort, recently published in the journal Cell, US-based researchers used affinity-purification mass spectrometry (AP-MS) to screen the interactions between Ebola virus and human host proteins — identifying 194 high-confidence protein-protein interactions. Further work concentrated on characterizing the interaction between the viral transcription regulator VP30 and the host ubiquitin ligase RBBP6. A crystal structure of the VP30-RBBP6 peptide complex revealed that RBBP6 mimics the viral nucleoprotein (NP), binding to the same interface of VP30.

Using a human macrophage model, it was shown that under-expression of endogenous RBBP6 stimulated viral transcription and viral replication, while over-expression strongly inhibited both. Interestingly, instead of revealing how the virus attacks the host, the team had identified a possible mechanism for the host to fight against the virus. According to the researchers “These results demonstrate the therapeutic potential of biologics that target this interface and identify additional PPIs that may be leveraged for novel therapeutic strategies”.  

READ THE FULL PAPER HERE


New mechanism driving p53 stability in cancerous cells


The tumor suppressor protein p53 plays a key role in protecting against cancer; however, mutant forms of this protein have the opposite action and are associated with the onset of many types of the disease. Although p53 is one of the most well studied human proteins, little is known about the mechanisms that govern its stability and function.

Researchers at the University of Wisconsin-Madison have shed new light on the molecular mechanisms that stabilize both wild type and mutant p53 proteins. Published in Nature Cell Biology, their research revealed that, during cell stress, an enzyme called PIPK1-α associates with p53 and produces the lipid messenger PIP2, which binds to the complex and promotes the interaction of p53 with small heat shock proteins (HSPs). It is this HSP binding that promotes the stability of the p53 protein.

The increased abundance and stability of mutated p53 is a primary driver for cancer and, as such, disruption of this binding pathway may provide a novel therapeutic strategy. In accordance with this assertion, the team demonstrated that inhibition of PIPK1-α or PIP2 association results in p53 destabilization.

READ THE FULL PAPER HERE


Preventing plant disease through protein-protein interactions


Fungal disease is a primary cause of agricultural crop damage, with estimates suggesting that over 600 million people could be fed each year by halting their spread in the world’s five most important crops. Fungal diseases propagate within plants through the secretion of effector molecules which suppress plant defense responses and modulate plant physiology to support fungal growth.

Some plants have developed resistance genes that encode intracellular immune receptors which recognize the infection ― typically leading to plant cell death at the infection site and thereby limiting spread of the pathogen. It has long been thought that these immune receptors recognize fungal effectors indirectly though the action of other host proteins; however, researchers at the Max Planck Institute for Plant Breeding Research have now revealed the facility for direct interaction between these two classes of protein.

The team examined the relationship between the effectors in powdery mildew fungi and immune receptors in the barley plant. Using engineered barley cells transfected with a number of different immune receptors and effectors it was shown that only matching pairs of receptors and effectors activated cell death. These protein-protein interactions were subsequently validated using bioluminescence. The findings of this study indicate that the transfer of immune receptor genes between different plant strains and species, or the generation of modified immune receptors, may provide a powerful new approach to combat fungal infections.

READ THE FULL PAPER HERE


Novel insights into the development of ALS


Amyotrophic lateral sclerosis (ALS), also known as motor neurone disease (MND) affects approximately 4.5 people per 100,000. The disease causes the neurons that control voluntary muscles to die, leading to muscle weakness and paralysis. The majority of people with ALS die within two to four years of their diagnosis. While the causes of ALS are not well understood, researchers are beginning to elucidate the molecular mechanisms that lead to neuronal death.

It is known that neuron degeneration is associated with the aggregation of nuclear RNA-binding proteins (RBPs), including one called FUS (Fused in Sarcoma). Mutant FUS proteins mislocalize and aggregate in the cytoplasm, causing particularly severe progression of ALS. In a study published in Acta Neuropathologica, an international team of scientists described how the mislocalization of FUS disrupts its interaction with other ALS-associated RBPs and it is these interactions which prevent aggregation of the FUS protein.

Furthermore, cells with mutant FUS also exhibit defective protein degradation, exacerbating the accumulation of FUS. Using drug-induced protein degradation, the research team were able to restore the homeostasis of RBPs, reducing the pathological processes linked to mutated FUS. These insights may enable the development of new therapeutic approaches to treat ALS.    

READ THE FULL PAPER HERE


Uncloaking the role of Merlin in rare nerve tumors


Neurofibromatosis type 2 is a rare genetic condition, affecting approximately 1 in 33,000 people worldwide. It is characterized by the formation of slow-growing benign tumors on nerve cells that are refractory to conventional chemotherapy. These tumors can lead to hearing loss and problems with balance.

The disease is caused by the inactivation of the tumor suppressor gene NF2, which encodes a protein called Merlin. As Merlin has no intrinsic catalytic activity, its tumor suppressor function is mediated through the proteins with which it interacts. Recently, researchers at Cincinnati Children’s Hospital have identified a number of potential Merlin binding partners which may ultimately help in the development of new disease treatment strategies.

Using proximity biotinylation followed by mass spectometry and direct binding assays, the team identified 52 cell junction proteins in close proximity to Merlin. The researchers are now further characterizing the role of these potential protein partners; however, one protein, ASPP2, which is a known regulator of the widely-studied p53 protein already stands out as a primary target for further study.

READ THE FULL PAPER HERE

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