News

A connection between life today and ancient changes in ocean chemistry. A new model for protein kinase activation. These findings by researchers at the San Diego Supercomputer Center (SDSC) and other UC San Diego departments were published in the Proceedings of the National Academy of Sciences (PNAS).

Faculty and graduate students from SDSC, UCSD's Bioengineering, Chemistry and Biochemistry, Biology and Pharmacology departments, as well as Scripps Institution of Oceanography, co-authored a PNAS paper describing the co-evolution of biology and geochemistry over geologic time. Using protein structures for the first time in such a study, Scripps graduate student Chris Dupont, SDSC researcher and Protein Data Bank director Philip Bourne, and their colleagues found that trace-metal usage by present-day organisms probably derives from major changes in ocean chemistry in the distant past.

The study sought to verify the theory that the rise in atmospheric oxygen some 2.3 billion years ago, and attendant shifts in ocean chemistry, led to changes in the types of metals used with protein structures. Such changes are hypothesized to have led to the diversification and increased complexity of the life we see today.

Protein structures are ideal for this study," Bourne said, "since they are much more conserved than protein sequences, traditionally used in such studies and, furthermore, metal binding can be inferred directly."

Using data generated by Dupont and Yang, the group established that the three superkingdoms of life - Archaea, Bacteria and Eukarya -- all use metals differently. The differences reflect the availability of such metals in the ocean as the respective superkingdoms evolved.

The authors conclude that, "these conserved trends are proteomic imprints of changes in trace-metal bioavailability in the ancient ocean that highlight a major evolutionary shift in biological trace-metal usage."

"Here, a biological phenomenon, photosynthesis, changed the availability of trace metals in the oceans," Dupont said, "resulting in a reciprocal change in biological evolution still observable today."

The researchers note that, "such studies linking the study of the earth sciences with that of the life sciences are limited and certainly no one has previously looked at this exciting area from the perspective of protein structure. We hope this will encourage others to undertake such interdisciplinary work."

Understanding Protein Kinase Activation

In a paper in the Cell Biology section of PNAS, a team led by Howard Hughes Medical Institute investigator Susan Taylor from the Chemistry and Biochemistry department at UCSD and Lynn Ten Eyck from SDSC, studied protein kinase activation in a set of protein kinases that were crystallized in active and inactive states.

Protein kinases represent a large and diverse class of proteins that play critical roles in signal transmission inside cells. All protein kinases catalyze the same chemical reaction in the cells of eukaryotes, such as animals and plants, but the malfunction of protein kinase activity can lead to a number of diseases. To date, numerous protein kinase structures have been solved in both active and inactive states, providing a general understanding of protein kinase functionality and its regulation.

In previous studies, researchers analyzed the kinases' tertiary structures. In this research, the UCSD scientists instead compared the surfaces of these molecules using a recently developed surface matching method based on an edge comparison and combination algorithm. "We have detected a set of 30 residues whose positions on the protein surface were highly conserved for different serine-threonine and tyrosine kinases," report the authors, noting that while some of the residues were known to be functionally important, others were not -- until now. "We have analyzed these residues and their possible roles in the activation process."

Based on their analysis, the authors were able to develop a general model of protein kinase activation in which the most important feature of the activation is a 'spine' formation that is dynamically assembled in all active kinases. The spine spans the molecule and plays a coordinating role in activated kinases. Conversely, in inactive kinases, the spine is disordered -- explaining "how stabilization of the whole molecule is achieved upon phosphorylation." Phosphorylation is the addition of a phosphate group to a protein or small molecule, and many enzymes and receptors are turned on by the process, making is one of the most important regulatory events in eukaryotes.