Protein Homeostasis

Protein aggregates represent an energetically stable, but non-functional alternative to the normal, functional, and soluble state of most proteins. In the context of human disease, aggregation occurs as proteins misfold or misassemble outside or inside the cell.

This research group provides important expertise in the analysis and characterization of proteins that traverse the mammalian secretory pathway. A third of the proteome of eukaryotic cells is targeted to the secretory pathway for maturation. These proteins are folded, processed, glycosylated, oxidized, and oligomerized in the endoplasmic reticulum (ER) prior to trafficking to other cellular locations (such as lysosomes) or as preparation for secretion.

Maintaining proper metal ion homeostasis is key to the survival of all organisms. In particular, the viability of many bacterial pathogens is linked to metal acquisition. The proteins that are involved in maintaining metal homeostasis control import and export (metallotransporters), target the delivery of metals to specific enzymes (metallochaperones), are involved in metallocenter assembly (accessory proteins), and regulate the expression of the other proteins in response to metal ion availability (metalloregulators). When metal-trafficking malfunctions several disease states result.

Regulation of protein degradation is required to ensure proper signaling and growth in all cells. For example, cells limit DNA replication to specific phases of growth by rapidly degrading proteins that trigger transitions between these phases. Improper degradation of DNA replication factors results in pathological conditions like cancer.

Lysosomal Storage Diseases subtheme investigates target areas that are important for the pharmaceutical and biotechnology industries. Lysosomal storage diseases are inherited metabolic diseases, generally caused by the loss of function of a single enzyme. Unlike most human diseases, which have complex etiologies, the underlying defect in lysosomal storage diseases is generally well characterized.

To understand human disease processes, it is necessary to understand the structure and function of the macromolecules and macromolecular interactions that lead to the disease. For example, organisms respond to their environment by activating signaling pathways that lead to specific cellular responses.

Biopharmaceuticals, the majority of which are protein drugs, constitute a distinct class of medicines due to their complex nature and often large size. As a result, the synthetic route of production, which provides a high level of structural fidelity to small molecule medicines, is typically unavailable for protein drugs.

Molecular chaperones and degradation enzymes, which are responsible for cellular protein homeostasis, work in networks and teams. Several faculty members in the Protein Homeostasis group investigate the detailed biochemical mechanisms of chaperones and degradation enzymes, providing insight into their potential as drug targets, and the networks in which any of these components work.

Pathogens rely on the host protein homeostasis machinery to support many of their protein folding and assembly reactions. In addition, pathogens often hijack host protein homeostasis machinery for alternative purposes. This reliance of pathogens on host protein homeostasis machinery presents novel opportunities for anti-infectives that function by modulating host chaperones and degradating enzymes in ways that are deleterious to the pathogen but tolerated by the host.