PhD: 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; D.Sc. honoris causa, Mount Holyoke College; Garvan-Olin Medal, American Chemical Society; NIH Director's Pioneer Award; Dorothy Crowfoot Hodgkin Award, The Protein Society; Fellow, Biophysical Society; Mildred Cohn Award, ASBMB; Elected Fellow, American Academy of Arts and Sciences; Outstanding Investigator Grant (Maximizing Investigators’ Research Award (MIRA)), National Institute of General Medical Sciences, NIH; Editor-in-Chief, The Journal of Biological Chemistry
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. 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. There are many challenges presented to a newly synthesized protein as it navigates its energy landscape to the native state in the cell, including the co-translational emergence of the protein from the ribosome and potential for conformational search before the chain is complete, the extremely high concentration of macromolecules and consequent crowding of the cellular milieu, the heterogeneous and limited volumes accessible to a folding chain, and the numerous molecular chaperones that interact with partially folded states and modulate their conformational exploration. We are using both ‘top down’ approaches by developing methods to observe a folding chain in cells and to perturb the cellular environment through genetic manipulation or environmental influences, and ‘bottom up’ approaches, wherein we mimic the components of the cell and examine their influence on folding.
In addition to this effort to describe the folding environment of the cell, we are doing detailed mechanistic studies of major classes of molecular chaperones. Present work focuses on the Hsp70s, which are ubiquitous and play a wide array of roles in facilitating the folding, membrane translocation, assembly and disassembly of complexes, and degradation of proteins in nucleotide-regulate manner, and in partnership with a complex network of partner chaperones. The Hsp70s are two-domain proteins, in which nucleotide binding to one domain allosterically modulates substrate affinity in the other domain. We deploy a wide array of biophysical methods, including NMR, fluorescence, EPR, and others, to dissect in detail how the interdomain allostery works.
Lastly, we recognize that protein folding in the cell does not always succeed, with many pathological consequences associated with misfolding. Important among these is aggregation. We are using the systems we develop to observe folding in the cell to examine the origins and mechanisms of protein aggregation in vivo, with a goal of better understanding misfolding-based diseases such as the many neurodegenerative diseases (Alzheimer’s, Huntington’s, Parkinson’s).
Lai AL, Clerico EM, Blackburn ME, Patel NA, Robinson CV, Borbat PP, Freed JH, Gierasch LM. Key features of an Hsp70 chaperone allosteric landscape revealed by ion mobility native mass spectrometry and double electron-electron resonance. JBC 292(21):8773-8785 (2017). http://www.ncbi.nlm.nih.gov/pubmed/28428246
Hingorani KS, Metcalf MC, Deming DT, Garman SC, Powers ET, Gierasch LM. Ligand-promoted protein folding by biased kinetic partitioning. Nat Chem Biol. 13: 369-371 (2017). http://www.ncbi.nlm.nih.gov/pubmed/28218913
Gierasch LM. Hsp70 molecular chaperones: Versatile modular nanomachines that mediate multiple biological functions. "Structure and Action of Molecular Chaperones" L. M. Gierasch, A. L. Horwich, C. Slingsby, S. Wickner, and D. Agard, Editors. World Scientific Publishers, Ch. 1, pp. 1-48 (2016).
Hebert DN, Clerico EM, Gierasch LM. Division of labor: ER-resident BiP co-chaperones martch substrates to fates based on specific binding sequences. Mol. Cell 63: 721-723 (2016). http://www.ncbi.nlm.nih.gov/pubmed/27588598
Chandrasekhar K, Ke H, Wang N, Goodwin T, Gierasch LM, Gershenson A, Hebert DN. Cellular folding pathway of a metastable serpin. Proc Natl Acad Sci U S A. 113:6484-9 (2016). [PubMed]
Hong J, Gierasch LM, Liu Z. Its Preferential Interactions with Biopolymers Account for Diverse Observed Effects of Trehalose. Biophys J. 109:144-53 (2015). [PubMed]
Zhuravleva A, Gierasch LM. Substrate-binding domain conformational dynamics mediate Hsp70 allostery. Proc Natl Acad Sci U S A. 112:E2865-73 (2015). [PubMed]
Cho Y, Zhang X, Pobre KF, Liu Y, Powers DL, Kelly JW, Gierasch LM, Powers ET. Individual and collective contributions of chaperoning and degradation to protein homeostasis in E. coli. Cell Rep. 11:321-33 (2015).[PubMed]
Clerico EM, Tilitsky JM, Meng W, Gierasch LM. How hsp70 molecular machines interact with their substrates to mediate diverse physiological functions. J Mol Biol. 427:1575-88 (2015). [PubMed]
Chien P, Gierasch LM. Challenges and dreams: physics of weak interactions essential to life. Mol Biol Cell. 25:3474-7 (2014). [PubMed]
Gershenson A, Gierasch LM, Pastore A, Radford S. Energy landscapes of functional proteins are inherently risky. Nat Chem Biol. 10:884-91 (2014). [PubMed]
Theillet FX, Binolfi A, Frembgen-Kesner T, Hingorani K, Sarkar M, Kyne C, Li C, Crowley PB, Gierasch L, Pielak GJ, Elcock AH, Gershenson A, Selenko P. Physicochemical Properties of Cells and Their Effects on Intrinsically Disordered Proteins (IDPs). Chem Rev. 114:6661-714 (2014). [PubMed]
General IJ, Liu Y, Blackburn ME, Mao W, Gierasch LM, Bahar I. ATPase subdomain IA is a mediator of interdomain allostery in Hsp70 molecular chaperones. PLoS Comput Biol. 10:e1003624. (2014). [PubMed]
Hingorani KS, Gierasch LM. Comparing protein folding in vitro and in vivo: foldability meets the fitness challenge. Curr Opin Struct Biol. 24:81-90 (2014). [PubMed]
Clerico EM and Gierasch LM. Structure and function of Hsp70 molecular chaperones. “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).
Hingorani K and Gierasch LM, How bacteria survive an acid trip. Proc. Natl. Acad. Sci. USA e-pub ahead of print 3/25/2013. [PNAS]
Budyak I, 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. [PubMed]
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. [PubMed]
Hebert DN, Chandrasekhar KD, and Gierasch LM. You got to know when to hold (or unfold) 'em… Mol. Cell, 48:3-4. [PubMed]
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
E.T. Powers, L.T. Powers and L.M. Gierasch. FoldEco: A Model for Proteostasis in E. coli, Cell Reports, 15 March 2012 online. [PubMed]