With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Scott Rychnovsky from University of California Irvine to develop new chemical tools to determine the structure of protein complexes. Understanding the function of protein-protein complexes is fundamental to understanding cellular processes. Although there are number of methods to study protein complexes, they all have significant limitations. The method being developed, chemical cross-linking, can be used under the widest variety of conditions and can capture dynamic states of the complexes. The chemical compound, a cross-linker, has two reactive ends that stick to parts of the protein. When the cross-linker sticks to two different proteins, it tells us that those proteins are close together in the complex. The important advance in this project is to make it much easier to identify the precise location the cross-linker sticks to in each protein. This information can be used to build a detailed model of the complex to better understand its behavior. The protein complex studied is the COP9 signalosome, which is important in the function of all cells in the body and mutations of this protein complex have been identified in important neurological disorders such as Alzheimer's disease and Down's syndrome. The program provides training for graduate students and undergraduates in chemistry and chemical biology. Promising undergraduate students are recruited from a local community college to participate in summer research, with the goal of stimulating their interest in scientific research careers.
The advent of Collision-Induced Dissociation (CID) cleavable crosslinkers has dramatically simplified the sequencing of cross-linked amino acids by liquid chromatography Mass Spectrometry (LCMS/MS). One objective of this proposal is to develop a family of CID-cleavable cross-linkers to facilitate the analysis of protein complexes. These new cross-linker reagents are broadly useful in the field of structural biology. The second research objective is to map out the dynamic structure of the COP9 signalosome (CSN). CSN is an important regulatory protein that catalyzes the hydrolysis of the Nedd8 protein from the cullin-RING ubiquitin ligase. CSN is found in all eukaryotes; the human form has eight canonical subunits, all of which appear to be required for function. CSN is important in regulating the cell cycle, in neuronal development and in DNA repair. Specific mutations in the CNS subunits have been implicated in a number of brain afflictions, including Alzheimer's disease and Down syndrome. A crystal structure was reported that provides a detailed static model of CSN. A goal of this project is to define the dynamic structure of the complete CSN.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
