个人简介

AB 1970, Mt. Holyoke College, PhD 1975, Harvard University

研究领域

Biophysical Chemistry/Conformational Analysis of Peptides and Proteins by NMR/CD and Other Spectroscopic Methods/Biophysical Approaches to Protein Folding and Localization In Vivo

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).

近期论文

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Chien P, Gierasch LM. Challenges and dreams: physics of weak interactions essential to life. Mol Biol Cell. 25:3474-7 (2014) Gershenson A, Gierasch LM, Pastore A, Radford S. Energy landscapes of functional proteins are inherently risky. Nat Chem Biol. 10:884-91 (2014). 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). 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). 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). Clerico EM and Gierasch LM. Structure and function of Hsp70 molecular chaperones. 揑nhibitors of Molecular Chaperones as Therapeutic Agents? T. D. Machajewski and Z. Gao, Editors, Royal Society of Chemistry Publishers, Ch. 3, pp. 65-125 (2014). Ferrolino MC, Zhuravleva A, Budyak IL, Krishnan B, Gierasch LM. 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 I, Krishnan B, Marcelino-Cruz A, Ferrolino M, Zhuravleva A, and Gierasch LM. Early folding events protect aggregation-prone regions of a β-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). Hebert DN, Chandrasekhar KD, and Gierasch LM. You got to know when to hold (or unfold) 'em? Mol. Cell 48:3-4 (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). Wang Q, Zhuravleva A, Gierasch LM. Exploring weak, transient protein-protein interactions in crowded in vivo environments by in-cell NMR spectroscopy. Biochemistry , Biochemistry, 50, 9225-9236 (2011). Smock RG, Blackburn ME and Gierasch LM. The conserved, disordered C-terminus of DnaK enhances in vitro chaperone function and cellular survival upon stress. J Biol Chem 286:31821 (2011). Zhuravleva A, Gierasch LM. Allosteric signal transmission in the nucleotide-binding domain of 70-kDa heat shock protein (Hsp70) molecular chaperones. PNAS 108:6987 (2011). Gierasch LM. A career pathway in protein folding: from model peptides to postreductionist protein science. Protein Sci 20:783 (2011). Krishnan B, Gierasch LM. Dynamic local unfolding in the serpin α-1 antitrypsin provides a mechanism for loop insertion and polymerization. Nat Struct Mol Biol 18:222 (2011). Gierasch, LM. How One Bad Protein Spoils the Barrel: Structural Details of β(2)-Microglobulin Amyloidogenicity. Mol Cell 41:129 (2011). Gershenson A, Gierasch LM. Protein folding in the cell: challenges and progress. Curr Opin Struct Biol 21:32 (2011). Smock RG, Rivoire O, Russ WP, Swain JF, Leibler S, Ranganathan R, Gierasch LM. An interdomain sector mediating allostery in Hsp70 molecular chaperones. Mol Sys Bio 6:414 (2010). Liu Y, Gierasch LM, Bahar I. Role of Hsp70 ATPase Domain Intrinsic Dynamics and Sequence Evolution in Enabling its Functional Interactions with NEFs. PLoS Comp Bio 6:9 (2010). Hong J, Gierasch LM. Macromolecular crowding remodels the energy landscape of a protein by favoring a more compact unfolded state. J Am Chem Soc 132:10445-52 (2010). Clérico EM, Zhuravleva A, Smock RG, Gierasch LM. Segmental isotopic labeling of the Hsp70 molecular chaperone DnaK using expressed protein ligation. Biopolymers 94: 742-52 (2010). Ghosh RP, Nikitina T, Horowitz-Scherer RA, Gierasch LM, Uversky VN, Hite K, Hansen JC, Woodcock CL. Unique physical properties and interactions of the domains of methylated DNA binding protein 2. Biochemistry 49: 4395-410 (2010). Eyles SJ, Gierasch LM. Nature's molecular sponges: Small heat shock proteins grow into their chaperone roles. PNAS 107: 2727-8 (2010).