Shedding some light on the ‘dark proteome’

MEMPHIS, Tenn. & LA JOLLA, Calif.—A multi-institutional team consisting of scientists from St. Jude Children’s Research Hospital and The Scripps Research Institute (TSRI), among others, recently kicked off the Human Dark Proteome Initiative (HDPI), an undertaking aimed at accelerating research into the portion of the proteome that does not take defined 3D structures. While these proteins comprise roughly a third of the human proteome, little has been known about them until now, when technological advancements such as nuclear magnetic resonance spectroscopy methods have advanced enough to allow for detailed study of the intrinsically disordered proteins (IDPs) and the intrinsically disordered regions (IDRs) of these molecules.

Dr. Peter Wright, who is the Cecil H. and Ida M. Green Investigator at TSRI and chair of the HDPI, says that given the scope of this undertaking, “a multi-institutional approach is absolutely essential.”

“The human dark proteome encompasses the more than one-third of proteins in the human proteome that are disordered and ‘unseen’ by traditional structural biology methods. Taking into account post-translational modifications and alternate splicing, the number of different proteins and protein variants involved is enormous—in the hundreds of thousands,” Wright explains. “Intrinsically disordered proteins play a central role in the dynamic regulation and organization of the cell and are directly implicated in debilitating diseases such as cancer, leukemia, diabetes, cardiovascular disease, infectious disease and several neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Advancing our understanding of the basic science of the dark proteome and its connection to disease, and translation of the discoveries into cures will require a coordinated multi-institutional—indeed, multinational—approach.”

The HDPI notes on its website that it has a seven-point mission for its work. The goals are to create a dark proteome research coordination network to foster collaborations; catalyze the establishment of centers of excellence to research the dark proteome; foster cooperation between federal agencies to provide funding for this research; advocate to increase attention for this work; stimulate the growth of infrastructure to support collaborative research into the dark proteome; coordinate outreach to private and philanthropic organizations to encourage independent support of this research; and collaborate with industry partners by serving as a liaison between researchers and pharmaceutical and biotech companies in this sphere.

“Our goal is to raise awareness about the potential societal impacts of a broad-based research infrastructure for these understudied proteins,” said Dr. Richard Kriwacki, a member of the St. Jude Department of Structural Biology and of the HDPI. “We also want to develop educational programs that will address the origins and potential cures of devastating diseases affected by these proteins that afflict large numbers of patients across the world.”

Wright says that the work done with the dark proteome in the past 15 to 20 years exposed the abundance of IDPs in the proteome and the regulatory and organizational processes they play a role in, as well as the diseases they could be associated with, but adds that “our understanding of the detailed molecular mechanisms by which the dark proteome functions in cellular regulation in health and disease remains very limited.”

Further investigation into the dark proteome is expected to reveal an “enormous number of potential targets,” enthuses Wright, who notes that therapeutic targets such as the proto-oncogene protein c-Myc, which he explains has been designated as a grand challenge drug target, are part of the dark proteome. Alpha-synuclein, an IDP, is the primary component of the protein aggregates associated with Parkinson’s disease, he adds, remarking that “Deeper understanding of the dark proteome and its role in neurodegeneration promises to lead to innovative new therapeutic approaches to treat these devastating diseases of aging.”