Lila M. Gierasch

Professor Department of Biochemistry and Molecular Biology, University of Massachusetts

Email: gierasch@biochem.umass.edu
L. Gierasch Biochemistry & Molecular Biology Dept Website
Gierasch Lab

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

Biophysical Approaches to Protein Folding and Localization

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 also 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?

Many proteins that are synthesized on cytoplasmic ribosomes are destined to function in non-cytoplasmic locations. We are interested in how the newly synthesized chain is directed to either extracellular or organellar sites. We have extensively examined biophysical properties of signal sequences, which facilitate the export of bacterial proteins, to elucidate their mode of action in vivo. We are now studying the interaction of signal sequences with proteins of the export pathway, including the bacterial proteins SecA and Ffh.

Representative publications:

Ignatova Z, Gierasch LM. Inhibition of protein aggregation in vitro and in vivo by a natural osmoprotectant. Proc Natl Acad Sci U S A. 2006 Aug 9; [Epub ahead of print]

Gierasch WW, Zimmerman DL, Ward SL, Vanheyningen TK, Romine JD, Leib DA. Construction and characterization of bacterial artificial chromosomes containing HSV-1 strains 17 and KOS. J Virol Methods. 2006 Aug;135(2):197-206. Epub 2006 May 2.

Gierasch LM, Passing of a gentle giant of Peptide Science: In memoriam, R. Bruce Merrifield.
Biopolymers. 2006 Jul 18; [Epub ahead of print]

Cavanaugh LF, Palmer AG 3rd, Gierasch LM, Hunt JF. Disorder breathes life into a DEAD motor.
Nat Struct Mol Biol. 2006 Jul;13(7):566-9.

Ignatova Z, Gierasch LM. Extended polyglutamine tracts cause aggregation and structural perturbation of an adjacent beta barrel protein. J Biol Chem. 2006 Mar 8;

Marcelino AM, Smock RG, Gierasch LM. Evolutionary coupling of structural and functional sequence information in the intracellular lipid-binding protein family. Proteins. 2006 May 1;63(2):373-84.

Swain JF, Gierasch LM. The changing landscape of protein allostery. Curr Opin Struct Biol. 2006 Feb;16(1):102-8. Epub 2006 Jan 19.

Swain JF, Schulz EG, Gierasch LM. Direct comparison of a stable isolated Hsp70 substrate-binding domain in the empty and substrate-bound states. J Biol Chem. 2006 Jan 20;281(3):1605-11. Epub 2005 Nov 6.

Rotondi KS, Gierasch LM. Natural polypeptide scaffolds: beta-sheets, beta-turns, and beta-hairpins.
Biopolymers. 2006;84(1):13-22.

R. G. Smock and L. M. Gierasch, Finding the Fittest Fold: Using the Evolutionary Record to Design New Protein Sequences, 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 b-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).

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 ).

Z. Ignatova and L. M. Gierasch, Aggregation of a slow-folding mutant of a b-clam protein proceeds through a monomeric nucleus, Biochemistry, 44, 7266-7274 (2005).

Y.T. Chou and L. M. Gierasch, The Conformation of a Signal Peptide Bound by Escherichia coli Preprotein Translocase SecA. Journal of Biological Chemistry, 280, 32753-32760 (2005).

Z. Ignatova and L. M. Gierasch, Monitoring protein stability and aggregation in vivo by real-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 Genetics , 54, 179-194 (2004).

J. Benach, Y. T. Chou, J. J. Fak, A. Itkin, D. D. Nicolae, P. C. Smith, G. Wittrock, D. L. Floyd, C. M. Golsaz, L. M. Gierasch, and J. F. Hunt, Phospholipid-Induced Monomerization and Signal Peptide-Induced Oligomerization of SecA, J. Biol. Chem. , 278, 3628-3638 (2003).

K. S. Rotondi, L. F. Rotondi, and L. M. Gierasch, Native Structural Propensity in Cellular Retinoic Acid Binding Protein 64-88: The Role of Locally Encoded Structure in the Folding of a ß -barrel Protein, Biophys. Chem. , 100, 421-436 (2003).

M. Kabani, S. H. Stewart, M. W. Morrow, D. L. Montgomery, R. Sivendran, M. D. Rose, L. M. Gierasch, and J. L. Brodsky, Dependence of Endoplasmic Reticulum Associated Degradation (ERAD) on the Peptide Binding Domain and Concentration of BiP, Mol. Cell Biol. , 14, 3437-3448 (2003).

K. S. Rotondi and L. M. Gierasch, The role of local sequence in the folding of cellular retinoic acid-binding protein 1: Structural propensities of reverse turns, Biochemistry, 42, 7976-7985 (2003).