The University of Massachusetts Amherst

Protein Homeostasis and the Secretory Pathway

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. The ER houses a variety of factors that aid in the maturation process including molecular chaperones, oxidoreductases, and carbohydrate binding and processing enzymes. As protein maturation is error-prone, the ER also supports a quality control process that evaluates the integrity of maturing nascent proteins and targets defective products for destruction. Protein destruction can lead to disease states such as cystic fibrosis, albinism, emphysema, heart disease, and the lysosomal storage diseases Fabry and Gaucher. In addition, if aberrant proteins are not properly removed, they can lead to formation of toxic aggregates either in the cell or in the extracellular space, and this is associated with a number of neurodegenerative diseases.

The Secretory Pathway subtheme comprises a number of laboratories that study various aspects of protein homeostasis using a variety of experimental systems and approaches. Cell biological approaches (Hebert) are used to follow the maturation and quality control processes in the mammalian secretory pathway with special emphasis on glycosylation and disulfide bond formation. Mass spectrometry (Kaltashov and Vachet) is used to analyze the structure of secretory cargo and aberrant extracellular aggregates. NMR (Gierasch) and single-molecule fluorescence (Gershenson) approaches are employed to map the folding pathway of wild type and mutant proteins associated with maladies such as serpinopathies to understand the etiologies associated with these illnesses. In addition, X-ray crystallography expertise (Garman) is being employed in the analysis of abnormalities associated with a number of lysosomal storage diseases.


Protein Homeostasis and the Secretory Pathway

Contact Info

Daniel Hebert, Department of Biochemistry and Molecular Biology
(413) 545-0079