NSF awards $4.5 million to researchers for study of protein folding mechanisms

In an effort to shed new light on what is known as the "protein folding problem" -- the deciphering of rules for encoding protein structure by its DNA sequence -- researchers led by Shimon Weiss of UCLA have been awarded more than $4.5 million by the National Science Foundation (NSF) Frontiers in Integrative Biological Research program to study the effects of the folding environment on protein folding mechanisms.

The award is one of three awarded by the NSF totaling $14 million given to researchers at UCLA, Stanford, UC Davis, Texas A&M, Michigan State University and the Scripps Research Institute to investigate under-studied or unanswered questions in biology.

The researchers are expected to use innovative approaches to address these questions by integrating scientific concepts across disciplines that include biology, mathematics and the physical sciences, engineering, social sciences and the informational sciences.

In all living organisms proteins begin to self-assemble or fold into their "native" three-dimensional structures as they emerge into their intracellular folding environment either from the exit tunnel of the ribosome -- the nano-machine responsible for translating genetic material into functional proteins -- or from nano-pores designed to transport proteins between intracellular compartments.

For most proteins the delicate balance of forces that controls and guides the folding process is highly sensitive to environmental solution conditions such as salt concentration, pH, temperature, viscosity, molecular crowding and the presence of folding co-factors and chaperones.

However, due to numerous experimental limitations, most protein folding studies are conducted under simple refolding solution (in-vitro) conditions, which differ conspicuously from the true in-vivo folding environment. To what degree do these differences affect the folding mechanisms of different proteins? To what degree are in-vitro refolding studies useful or valid in light of these differences? Can we identify in-vitro solution conditions that adequately mimic the in-vivo folding environment? These are all questions critical to continued advances in the field of protein folding that will be investigated in this project.

Led by biophysicist Weiss, a member of UCLA's California NanoSystems Institute, the team will use a host of recent methodological advances pioneered and advanced by members of Frontiers in Integrative Biological Research consortium. These advances will allow the detection and study of protein folding processes under physiologically relevant solution conditions and with the spatial and temporal resolutions required to make unequivocal conclusions about the effects of environmental differences on protein folding mechanisms.

This research consortium will study the unfolded states of three different proteins in-vitro in the absence of chemical denaturants, under a variety of solution conditions, with different concentrations of various additives, and while the proteins are being made directly on the ribosome itself. By comparing such in-vitro studies to protein folding experiments conducted within mitochondria, this project seeks to understand the major differences between in-vitro and in-vivo folding environments and the effects of such differences on protein folding mechanisms.

It is expected that this project will lead to the development of novel tools and methods as well as a general approach for studying complex biological processes on the molecular level and to the dissemination of these research tools to the broad scientific community.

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The UCLA group overseen by Weiss, which has pioneered and continues to develop the use of high-resolution single-molecule spectroscopies to study protein folding processes, includes Dr. Carla Koehler, an expert in the field of mitochondrial protein transport.

Others involved in the Weiss study are Dr. Vijay Pande of Stanford, founder and director of the Folding@Home distributed super-computing project, which harnesses the power of over 200,000 computers worldwide to conduct large-scale protein folding simulations; Dr. Arthur E. Johnson of Texas A&M University, who pioneered the method of non-natural amino-acid labeling and has recently succeeded in applying this technique to study the conformations of ribosome-bound nascent proteins; Dr. Olgica Bakajin of the UC Davis/NSF Center for Biophotonics Science and Technology continues to push the limits of experimental protein folding kinetics with her innovative microfluidic mixing devices; Dr. Lisa J. Lapidus of Michigan State University, who has pioneered a spectroscopic technique which can determine the rates for intra-molecular contact formation in peptides, and Dr. Jeff Kelly of the Scripps Research Institute, a pioneer in the field of synthetic peptide chemistry and in-vivo protein folding.

About the California NanoSystems Institute

The CNSI is a research center whose mission is to encourage university collaboration with industry and to enable the rapid commercialization of discoveries in nanosystems. The CNSI members who are on the faculty at UCLA represent a multi-disciplinary team of some of the world's preeminent scientists. The work conducted at the CNSI represents world-class expertise in five topical thrust group areas of nanosystems-related research: 1) Energy, 2) Environment and Nanotoxicology, 3) NanoBiotechnology and Biomaterials, 4) NanoMechanical and Nanofluidic Systems, and 5) NanoElectronics, Photonics and Architectonics. For additional information, please visit www.cnsi.ucla.edu.

About UCLA

California's largest university, UCLA enrolls approximately 38,000 students per year and offers degrees from the UCLA College of Letters and Science and 11 professional schools in dozens of varied disciplines. UCLA consistently ranks among the top five universities and colleges nationally in total research-and-development spending, receiving more than $820 million a year in competitively awarded federal and state grants and contracts. For every $1 state taxpayers invest in UCLA, the university generates almost $9 in economic activity, resulting in an annual $6 billion economic impact on the Greater Los Angeles region. The university's health care network treats 450,000 patients per year. UCLA employs more than 27,000 faculty and staff, has more than 350,000 living alumni and has been home to five Nobel Prize recipients.


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