Xiaokun Shu receives NIH New Innovator Award to study protein interactions

Xiaokun Shu, PhD, has been named a recipient of the 2012 National Institutes of Health (NIH) Director’s New Innovator award, which will provide up to $1.5 million in research funding over the next five years.

Shu, a faculty member in the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry, will use the funding to develop a new technology to identify dynamic interactions between proteins in human cells.

In particular, Shu’s NIH-funded work will seek to detect weakly binding and short-lived interactions that can be difficult to detect via current techniques but which can play vital roles in health and disease.

This marks the third year in a row that a young School faculty member has won this highly selective funding, designed “to support exceptionally creative new investigators who propose highly innovative projects that have the potential for unusually high impact.” This year it was awarded to 51 scientists nationwide.

From genome to interactome: how proteins do their jobs

The new NIH funding will fuel research in the Shu Lab focused on mapping what has been dubbed the protein interactome, that is, the networks of interactions between protein molecules inside living cells.

While a decade-long international effort sequenced the human genome at the turn of this century—identifying more than 20,000 genes that encode (express) proteins—Shu notes that this only marked a new beginning in biological exploration.

Thus, there’s proteomics, the effort to discover the complex structures and functions of the tens of thousands of protein molecules those genes express. This is further complicated by the fact that different proteins are expressed at different times to different extents in different types of cells. And proteins are hardly static; they’re constantly interacting with one another, undergoing changes to their chemical forms and thus their functions.

Just like individual people living in a society, proteins in cells work together to get things done in groups and networks analogous to human organizations and project teams, thus the term “interactome.”

“For proteins to carry out diverse cellular functions, they need to interact with each other, forming various networks or signaling pathways,” says Shu.

By identifying protein-protein interactions—creating maps that look like interconnected starbursts [see example]—scientists can help to determine a given protein’s functions and relative importance by the type and number of associations it has. As a Science magazine feature put it: “It’s like profiling a protein by cataloging its Facebook friends.”

interaction network

An interaction network involving human chaperone proteins. Generated by the UCSF RBVI based on supplemental data from Echeverria, et al. (2011) using the Cytoscape platform.

New effort to study weak, transient, dynamic protein interactions

Some proteins form complexes with strong and durable interactions, such as a nuclear pore complex—made up of dozens of different kinds of proteins and hundreds of individual molecules—that regulates the passage of molecules into and out of a cell’s nucleus.

Other proteins interact in swiftly formed networks or rapid cascades of signaling inside and between cells, so that our bodies can respond to the environment. Those interactions can be transient—short-lived and dependent on a cascade of chemical changes.

“There are three types of protein-protein interactions,” says Shu. “You have these permanent complexes, with very strong interactions. Second, you have strong transient interactions…. And the third category, weak transient interactions,” which can still be very significant for function.

“If the [protein] interaction is weak, it’s much easier to regulate,” says Shu. “A lot of cells need signaling pathways to perform very dynamically, because they need to change in response to different conditions.”

The current primary technology for detecting networks of protein-protein interactions involves tagging a target protein of interest that is then used like bait. It is fished out of a cell’s contents along with its interacting proteins, which are then identified using mass spectrometry.

But those proteins that are more weakly bound yet vital to dynamic interactions may not be picked up, notes Shu. Indeed, some experts estimate we’re currently only detecting 10 to 20 percent of interacting proteins.

“That’s why we want to develop a technology that’s based on a new principle, that does not depend on affinity [binding strength] so that we can detect both weak and strong interactions,” says Shu.

New technology will be applied to chaperone networks

The details of that technology remain under development and under wraps while a patent is sought, but Shu says that as a test case his lab will seek to map and identify a set of protein-protein interactions known as chaperone networks.

When they’re first expressed in cells, proteins are long chains of amino acids that then fold up into the complex structures that determine their particular functions. Some proteins need the aid of chaperone proteins to fold properly. “Chaperone is a general term, which includes many proteins [acting] as a complex,” says Shu.

Chaperone proteins are expressed in greater quantities when cells are under stress from conditions including heat, infection, and inflammation, which interfere with some proteins’ ability to fold.

Indeed, Shu notes that pathogens have their own chaperone networks to help their proteins fold in the foreign environment of a human cell. They may even hijack a host cell’s chaperones or perturb a chaperone network used to help fold critical enzymes that defend against invaders. So identifying the key players in chaperone networks could help drug developers target proteins involved in infections.

“We are also studying other protein interaction networks,” says Shu. “The chaperone network involves weak and transient interactions, so it is a good start in demonstrating our technology."

In 2011, the New Innovator award went to Shu’s department colleague, Bo Huang, PhD, and in 2010 the five-year NIH funding went to Michael Fischbach, PhD, a faculty member in the Department of Bioengineering and Therapeutic Sciences, a joint department of the UCSF Schools of Pharmacy and Medicine.

About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.