Distinguished Professor, Department of Biochemistry and Molecular Biology
and Department of Chemistry, University of
L. Gierasch Biochemistry & Molecular Biology Web Site
L. Gierasch Lab Web Site
Ph.D.: Harvard University
Honors: A.P. Sloan Fellowship; Vincent du Vigneaud Award for Young Investigators in Peptide Chemistry; Guggenheim Fellowship; Fellow, American Association for the Advancement of Science; NIH Pioneer Award; Dorothy Hodgkin Award of the Protein Society
Protein folding in the cell and molecular chaperone functions
The protein folding problem, namely how amino acid sequence determines the three-dimensional structure of a protein, is not fully understood despite many years of effort. We are addressing this problem in a variety of ways in our laboratory: We study the conformational preferences of model peptides in order to explore how local sequence guides folding. We are also carrying out detailed studies in the in vitro folding of a predominantly b -sheet protein with a very simple topology. Methods we use in all of our folding work include circular dichroism, fluorescence, and nuclear magnetic resonance.
We are particularly interested in how a protein folds in vivo. In recent years, a class of proteins called molecular chaperones has been found to facilitate protein folding in vivo. We are addressing several questions concerning chaperones: How do they recognize and bind incompletely folded polypeptides? Do different classes of chaperones bind to their substrates in distinct ways? How do chaperones interact with their co-chaperones? Is the mechanism of chaperone-mediated folding different from that of the isolated protein?
Y. H. Cho, X. Zhang, K. F. R. Pobre, Y. Liu, J. C. Genereux, L. M. Gierasch, E. T. Powers, and J. W. Kelly. Individual and collective contributions of chaperoning and degradation to protein homeostasis in E. coli. Cell Reports, 11, 321-333 (2015).
E. M. Clerico, W. Meng, J. M. Tilitsky, and L. M. Gierasch. How Hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. J. Mol. Biol., 427, 1575-1588 (2015).
P. Chien and L. M. Gierasch. Challenges and dreams: physics of weak interactions essential to life. Mol. Biol. Cell, 25, 3474-3477 (2014).
A. Gershenson, L. M. Gierasch, A. Pastore, and S. E. Radford. Energy Landscapes of Functional Proteins Are Inherently Risky. Nat. Chem. Biol., 10, 884-91 (2014).
I. General, Y. Liu, M. Blackburn, L. M. Gierasch, and I. Bahar. ATPase subdomain IA is a mediator of interdomain allostery in Hsp70 molecular chaperones. PLoS Comput Biol 10: e1003624 (2014).
F.-X. Theillet, A. Binolfi, T. Frembgen-Kesner, K. Hingorani, M. Sarkar, C. Kyne, C. Li, P. Crowley, L. Gierasch, G. Pielak, A. Elcock, A. Gershenson, P. Selenko. Physicochemical and biological properties of cells and their effects on IDPs. Chem. Reviews, 113, 6661-714 (2014).
E. M. Clerico and L. M. Gierasch. Structure and function of Hsp70 molecular chaperones. In “Inhibitors of Molecular Chaperones as Therapeutic Agents”, T. D. Machajewski and Z. Gao, Editors, Royal Society of Chemistry Publishers, Ch. 3, pp. 65-125 (2014).
K. S. Hingorani and L. M. Gierasch. Comparing protein folding in vitro and in vivo: foldability meets the fitness challenge. Curr. Opin. Struct. Biol., 24, 81-90 (2014).
M. C. Ferrolino, A. Zhuravleva, I. L. Budyak, B. Krishnan, and L. M. Gierasch. Delicate balance between functionally required flexibility and aggregation risk in a β-rich protein. Biochemistry, 52, 8843-54 (2013).
Budyak IL, Zhuravleva A, and Gierasch LM, The role of aromatic-aromatic interactions in strand-strand stabilization of β-sheets. J Mol Biol. 425:3522-35 (2013)
Hingorani K and Gierasch LM, How bacteria survive an acid trip. Proc. Natl. Acad. Sci. USA 110:5279-80 (2013).
Budyak IL, Krishnan B, Marcelino-Cruz A, Ferrolino M, Zhuravleva A, and Gierasch LM. Early folding events protect aggregation-prone regions of a beta-rich protein. Structure 21:476-485 (2013).
Zhuravleva A, Clerico EM, and Gierasch LM. An interdomain energetic tug-of-war creates the allosterically active state in Hsp70 molecular chaperones. Cell 151:1296-307 (2012).
Horwich AL, Buchner J, Smock RG, Gierasch LM, and Saibil HR. Chaperones and Protein Folding. Comprehensive Biophysics Vol. 3, V. Daggett, Editor, Elsevier, pp. 212-237 (2012).
Powers ET, Powers DL, and Gierasch LM. FoldEco: A model for proteostasis in E. coli. Cell Reports 1:265-276 (2012).
Maki JL, Krishnan B, and Gierasch LM. Using a low denaturant model to explore the conformational features of translocation-active SecA. Biochemistry 51:1369-79 (2012).
Q. Wang, A.Zhuravleva, and L. M. Gierasch.Exploring weak, transient protein-protein interactions in crowded in vivo environments by in-cell NMR spectroscopy, Biochemistry, 50, 9225-9236 (2011).
R. G. Smock, M. Blackburn, and L. M. Gierasch. Conserved, disordered C-terminus of DnaK enhances cellular survival upon stress and DnaK in vitro chaperone function. J. Biol. Chem., 286, 31821-31829 (2011).
A. Zhuravleva and L. M. Gierasch. Allosteric signal transmission in the nucleotide-binding domain of Hsp70 molecular chaperones. Proc. Natl. Acad. Sci. U.S.A., 108, 6987-92 (2011).
L. M. Gierasch.A career pathway in protein folding: From model peptides to post-reductionist protein science. Protein Science, 20, 783-790 (2011).
A. Gershenson and L. M. Gierasch. Protein folding in the cell: challenges and progress. Curr. Opin. Struct. Biol.,21, 32-41 (2011).
B. Krishnan and L. M. Gierasch. Dynamic local unfolding in the serpinalpha-1 antitrypsin provides a mechanism for loop insertion.Nat. Struct. Mol. Biology,18, 222-226 (2011).
Y. Liu, L. M. Gierasch, and I. Bahar. Interplay between structural dynamics and sequence co-evolution in nucleotide exchange factor/HSP70 interactions. PLOS Comp. Biol., e1000931 (2010).
R. G. Smock, O. Rivoire, W. P. Russ, J. F. Swain, S. Liebler, R. Ranganathan, and L. M. Gierasch.An interdomain sector mediating allostery in Hsp70 molecular chaperones.Mol. Syst. Biol., 6, 414 (2010).
J. Hong and L. M. Gierasch.Macromolecular crowding remodels the energy landscape of a protein by favoring a more compact unfolded state. J. Amer. Chem. Soc., 132, 10445-52 (2010).
E. M. Clérico, A. Zhuravleva, R. G. Smock, and L. M. Gierasch. Segmental isotopic labeling of the Hsp70 molecular chaperone DnaK using expressed protein ligation. Biopolymers-Peptide Science, 94, 742-52(2010).
R. P. Ghosh, T. Nikitina, R. A. Horowitz-Scherer, L. M. Gierasch, V. N. Uversky, K. Hite, J. C. Hansen, and C. L. Woodcock. Unique physical properties and interactions of the domains of methylated DNA binding protein 2. Biochemistry, 49, 4395-4410 (2010).
L. M. Gierasch and A. Gershenson.Post-reductionist protein science, or how to put Humpty Dumpty back together again.Nat. Chem. Biol., 5, 774-777 (2009).
R. G. Smock and L. M. Gierasch.Sending signals dynamically: how protein motions mediate cellular communication pathways, Science, 324, 198-203 (2009).
Gierasch LM, Gershenson A. Post-reductionist protein science, or putting Humpty Dumpty back together again. Nat. Chem. Biol. 5:774-7 (2009).
Hebert DN, Gierasch LM. The molecular dating game: an antibody heavy chain hangs loose with a chaperone while waiting for its life partner. Mol. Cell 34:635-6 (2009).
Clérico EM, Szymanska A, Gierasch LM. Exploring the interactions between signal sequences and E. coli SRP by two distinct and complementary cross-linking methods. Biopolymers 92:201-11 (2009).
Smock RG, Gierasch LM. Sending signals dynamically. Science 324: 198-203 (2009).
Ignatova Z, Gierasch LM. A Method for Direct Measurement of Protein Stability In Vivo. Methods Mol. Biol. 490: 165-78 (2009).
Krishnan B, Gierasch LM. Cross-Strand Split Tetra-Cys Motifs as Structure Sensors in a β-Sheet Protein. Chem Biol 15, 1104-15 (2008).
Ghosh RP, Horowitz-Scherer RA, Nikitina T, Gierasch LM, Woodcock CL. Rett syndrome-causing mutations in human MeCP2 result in diverse structural changes that impact folding and DNA interactions. JBC 283, 20523-34 (2008).
Hinz J, Gierasch LM, Ignatova Z. Orthogonal Cross-Seeding: An Approach To Explore Protein Aggregates In Living Cells. Biochemistry 47, 4196-4200 (2008).
Gierasch LM, Deber CM, Brodsky B. Celebrating the scientific legacy of Elkan R. Blout. Biopolymers 89, 323 (2008).
Marcelino AM, Gierasch LM. Roles of β-turns in protein folding: From peptide models to protein engineering. Biopolymers 89, 380-91 (2008).
Ignatova Z, Thakur AK, Wetzel R, Gierasch LM. In-cell aggregation of a polyglutamine-containing chimera is a multi-step process initiated by the flanking sequence. JBC 282, 36736-43 (2007).
Clerico EM, Maki JL, Gierasch LM. Use of synthetic signal sequences to explore the protein export machinery. Biopolymers 90, 307-19 (2007).
Ignatova Z, Gierasch LM. A Method for Direct Measurement of Protein Stability In Vivo. Methods Mol. Biol. in press (2007).
Ignatova Z, Gierasch LM. A Fluorescent Window into Protein Folding and Aggregation in Cells. Methods Cell Biol. in press (2007).
Ignatova Z, Gierasch LM. Effects of osmolytes on protein folding and aggregation in cells. Methods Enzymol 428, 355-72 (2007).
Swain JF, Dinler G, Sivendran R, Montgomery DL, Stotz M, Gierasch LM. Hsp70 chaperone ligands control domain association via an allosteric mechanism mediated by the interdomain linker. Mol Cell 26, 27-39 (2007).
Gierasch LM. In memoriam: A true statesman of science, Elkan R. Blout. Biopolymers 85, vi (2007).
Krishnan B, Szymanska A, Gierasch LM. Site-specific fluorescent labeling of poly-histidine sequences using a metal-chelating cysteine. Chem Biol Drug Des 69, 31-40 (2007).
Ignatova Z, Krishnan B, Bombardier JP, Marcelino AM, Hong J, Gierasch LM. From the test tube to the cell: Exploring the folding and aggregation of a beta-clam protein. Biopolymers 88, 157-63 (2007).
Lin BR, Gierasch LM, Jiang C, Tai PC. Electrophysiological Studies in Xenopus Oocytes for the Opening of Escherichia coli SecA-Dependent Protein-Conducting Channels. J Membr Biol 214, 103-13 (2006).
Ignatova Z, Gierasch LM. Inhibition of protein aggregation in vitro and in vivo by a natural osmoprotectant. Proc Natl Acad Sci, 103, 13357-61 (2006).
Cavanaugh LF, Palmer AG 3rd, Gierasch LM, Hunt JF. Disorder Breathes Life into a DEAD Motor, Nat Struct Mol Biol, 13, 566-9 (2006).
I. L. Mainprize, D. R. Beniac, E. Falkovskaia, R. M. Cleverley, L. M. Gierasch, F. P. Ottensmeyer, and D. W. Andrews, The Structure of E. coli Signal Recognition Particle Revealed by Scanning Transmission Electron Microscopy, Mol. Biol. Cell, 17, 5063-74 (2006).
Z. Ignatova and L. M. Gierasch, Extended PolyQ Tracts Cause Aggregation and Structural Perturbation of a Neighboring β–Barrel Protein, J. Biol. Chem., 281, 12959-67 (2006).
A. C. Marcelino, R. G. Smock, and L. M. Gierasch, Evolutionary Coupling of Structural and Functional Sequence Information in the Intracellular Lipid-Binding Protein Family, Proteins: Structure Function Bioinformatics, 63, 373-384 (2006).
J. F. Swain and L. M. Gierasch, The Changing Landscape of Protein Allostery. Curr. Opin. Struct. Biol. 16, 102-108 (2006).
J. F. Swain, E. G. Schulz, and L. M. Gierasch, Direct Comparison of a Stable Isolated Hsp70 Substrate-binding Domain in the Empty and Substrate-bound States, J. Biol. Chem., 281, 1605-11 (2006).
K. S. Rotondi and L. M. Gierasch, Natural Polypeptide Scaffolds: β-Sheets, β-Turns, and β-Hairpins, Peptide Science, 84, 13-22 (2006).
R. G. Smock and L. M. Gierasch, Finding the Fittest Fold: Using the Evolutionary Record to Design New Proteins, Cell, 122, 832-834 (2005).
J. F. Swain and L. M. Gierasch, First Glimpses of a Chaperonin-bound Folding Intermediate, Proc. Natl. Acad. Sci. USA, 102, 13715-13716 (2005).
Y.-T. Chou and L. M. Gierasch, The Conformation of a Signal Peptide Bound by Escherichia coli Preprotein Translocase SecA, J. Biol. Chem., 280, 32753-32760 (2005).
Z. Ignatova and L. M. Gierasch, Aggregation of a Slow-folding Mutant of a β-Clam Protein Proceeds through a Monomeric Nucleus, Biochemistry, 44, 7266-7274 (2005).
N. Sinha, C. V. Grant, K. S. Rotondi, L. Feduik-Rotondi, L. M. Gierasch, and S. J. Opella, Peptides and the Development of Double- and Triple- Resonance Solid-State NMR of Aligned Samples, J. Pept. Res., 65, 605-620 (2005).
K. S. Rotondi and L. M. Gierasch, A Well-Defined Amphipathic Conformation for the Calcium-Free Cyclic Lipopeptide Antibiotic, Daptomycin, in Aqueous Solution, Peptide Science, 80, 374-385 (2005).
K. S. Rotondi and L. M. Gierasch, Solution Structure of Daptomycin, in Peptide Revolution: Genomics, Proteomics & Therapeutics, (M. Chorev and T. Sawyer, eds.), pp. 447-449 (2004).
J. J. Fak, A. Itkin, D. D. Ciobanu, E. C. Lin, X.-J. Song, Y.-T. Chou, L. M. Gierasch, and J. F. Hunt, Nucleotide Exchange from the High-Affinity ATP-Binding Site in SecA Is the Rate-Limiting Step in the ATPase Cycle of the Soluble Enzyme and Occurs through a Specialized Conformational State, Biochemistry, 43, 7307-27 (2004).
Z. Ignatova and L. M. Gierasch, Monitoring Protein Stability and Aggregation In Vivo byReal-Time Fluorescent Labeling, Proc. Natl. Acad. Sci. USA, 101, 523-528 (2004).
K. Gunasekaran, A. T. Hagler, and L. M. Gierasch, Sequence and Structural Analysis of Cellular Retinoic Acid Binding Proteins Reveals a Network of Conserved Hydrophobic Interactions, Proteins: Structure Function and Bioinformatics, 54, 179-194 (2004).