Al Burlingame, PhD
My research interests focus on the development of state of the art methodologies in mass spectrometry for use in advancing our global knowledge of human biology, specifically the dynamic, epigenetic modulation and regulation of the proteome. This occurs in the context of deciphering molecular alterations and defects that underlie disease and cancer.
Technologically new internal energy deposition techniques (electron capture and transfer) have spawned development of orthogonal ways to enable sequencing and structural characterize of very large peptides and small to intermediate molecular weight proteins directly.
On-going particular projects include research on the mammalian and human proteomes including large macromolecular assemblages that are dynamic, functional entities in cells. These include the signal processing protein machines, the synapse, and RNA/protein complexes such as the spliceosome. We also study host-pathogen interactions.
In addition, we study the nature and role of posttranslational modulation in cell biology including protein complexes in signaling networks and those modulating changes in histone modification states in chromatin biology.
Many covalent modifications are under active investigation including phosphorylation (phosphoproteomics), sulfation, O-GlcNAcylation, methylation, acetylation, ubiquitinylation, lipidation and controlled proteolysis. For some classes of proteins, posttranslational occupancies occur in multiple "combinatorial" motifs and function in a concerted, synergistic manner, e.g., the "histone code" in chromatin biology. We are interested in defining these isoform occupancies and the discovery of the effector proteins that "read" this epigenetic code.
Finally we employ residue specific chemical cross-linking to obtain distance constraints that permit homology modeling of protein complexes that have not yielded to x-ray crystallography.
Once a discovery phase is carried out, important biological insight can be deduced from studies of the dynamics of posttranslational occupancies in a site specific manner. Mass spectrometry provides the basic tools to conduct these studies without the need for sets of antibodies required for immunochemical strategies. Stable isotopic (e.g., 15N) measurements are important for studies of global turnover studies even in vivo. Projects include studies of signaling in Alzheimer, Parkinson and prion mouse models.
Finally we collaborate with investigators to develop chemical biological approaches for the linkage of enzyme systems to their cellular substrates (kinases, proteolytic enzymes, ubiquitinylation, etc.).