Lila Gierasch
Distinguished Professor
University of Massachusetts
Talk Information
Exploration of Selectivity and Methods for Targeting Disease
18 June 2025, 04:20pm - 04:45pm, in the Pacific Jewel Ballroom
L49 – How Hsp70 Molecular Chaperones Bind Substrates with Selective Promiscuity
Professor Lila M. Gierasch is a Distinguished Professor in the Departments of Biochemistry & Molecular Biology and Chemistry at the University of Massachusetts Amherst. Her research focuses on understanding the mechanisms of protein folding within the cellular environment, with implications for diseases related to protein misfolding.
Academic Background
Dr. Gierasch earned her B.A. in Chemistry from Mount Holyoke College in 1970 and her Ph.D. in Biophysics from Harvard University in 1975. She began her academic career at Amherst College, followed by positions at the University of Delaware and the University of Texas Southwestern Medical Center. In 1994, she joined the University of Massachusetts Amherst, where she continues her research and teaching endeavors.
Research Focus
Professor Gierasch's research addresses the protein folding problem, exploring how amino acid sequences determine the three-dimensional structures of proteins. Her lab employs techniques such as circular dichroism, fluorescence spectroscopy, and nuclear magnetic resonance to study protein folding both in vitro and in vivo. A significant aspect of her work involves investigating the role of molecular chaperones, particularly Hsp70s, in assisting protein folding and maintaining cellular proteostasis.
Notable Contributions
Dr. Gierasch has made significant contributions to the understanding of protein folding mechanisms and the function of molecular chaperones. Her research has elucidated how chaperones recognize and interact with unfolded proteins, providing insights into the maintenance of protein homeostasis and the prevention of aggregation-related diseases such as Alzheimer's and Parkinson's.
Awards and Honors
Professor Gierasch's work has been recognized with numerous awards, including:
- Vincent du Vigneaud Award, American Peptide Society, 1984
- Guggenheim Fellowship, 1986
- Garvan-Olin Medal, American Chemical Society, 2006
- NIH Director's Pioneer Award, 2006
- Mildred Cohn Award, American Society for Biochemistry and Molecular Biology, 2014
- Ralph F. Hirschmann Award in Peptide Chemistry, American Chemical Society, 2018
- R. Bruce Merrifield Award, American Peptide Society, 2019
Professional Engagements
Beyond her research, Dr. Gierasch served as the Editor-in-Chief of the Journal of Biological Chemistry from 2016 to 2021. She is an elected member of the American Academy of Arts and Sciences and the National Academy of Sciences, reflecting her esteemed position in the scientific community.
Through her pioneering research and leadership, Professor Lila M. Gierasch continues to advance the field of protein chemistry, contributing to our understanding of protein folding and its implications for human health.
How Hsp70 Molecular Chaperones Achieve Selectively Promiscuous Substrate Binding
Departments of Biochemistry & Molecular Biology and Chemistry, University of Massachusetts Amherst, Amherst, MA, USA
Hsp70 molecular chaperones perform diverse roles in protein homeostasis, including facilitating of folding, inhibition of aggregation, targeting to organelles, and more. Their functions rely on their ability to bind to relatively short sequences in their substrates with a nucleotide-gated affinity. In general, Hsp70s bind short hydrophobic segments on their substrates; however, the detailed mechanism of client recognition is more complex, and the distinctions among modes of client recognition among Hsp70s are poorly understood.
While some Hsp70s bind proteins selectively, there are variations in the degree of client selectivity observed among Hsp70 isoforms. We previously observed that the E. coli Hsp70, DnaK, binds not infrequently to substrate sequences in a C-to-N, non-canonical orientation, as well as in an N-to-C canonical orientation (Clerico et al., Proc. Natl. Acad. Sci. U.S.A. 118, e2016962118 [2021]). Of particular use in the study of synthetic peptide models bound to DnaK was NMR analysis of selectively δ1-methyl labeled (1H,13C) isoleucines that are near the substrate recognition cleft. The δ1-methyl resonance positions reported on the identity of the residue bound in the central pocket of the binding cleft, as well as the orientation of the bound peptide.
In recent work, we have compared the substrate-binding properties of the major cytoplasmic mammalian Hsp70s, Hsc70 and HspA1, to those of DnaK. Emerging from this work has been the working hypothesis that Hsc70s are less stringent in their binding than DnaK, with a greater diversity of binding modes, which may arise from the enlargement of the human proteome and wider array of physiological functions for these Hsp70s relative to that of E. coli.
[Supported by NIH grant R35 GM118161]