个人简介

2013-present Rev. John Cardinal O'Hara CSC Professor of Biochemistry, University of Notre Dame 2013-present Concurrent Professor, Chemical & Biomolecular Engineering, University of Notre Dame 2010-2013 Rev. John Cardinal O'Hara CSC Associate Professor of Biochemistry,University of Notre Dame 2008-2010 Associate Professor, University of Notre Dame 2006-2008 Assistant Professor, University of Notre Dame 2001-2006 Clare Boothe Luce Assistant Professor of Biochemistry, University of Notre Dame 1997-2001 Postdoctoral Fellow, Massachusetts Institute of Technology 1997 Ph.D. in Molecular Biophysics, University of Texas Southwestern Medical Center 1991 B.S. in Chemistry, Georgia Institute of Technology Selected Awards 2013 Michael and Kate Barany Award for Young Investigators, Biophysical Society 2003-2007 American Heart Association National Scientist Development Award 2003-2008 NSF CAREER Award 1998-2001 NIH NRSA Postdoctoral Fellowship 1994-1997 NIH Biophysics Predoctoral Training Fellowship

研究领域

Biochemistry Physical/Analytical Chemistry

Proteins are long flexible polymers of amino acids, yet each must fold into a complex 3D shape in order to carry out a specific catalytic, binding, or structural activity. Experiments with purified proteins have demonstrated that the information needed for a given protein to obtain its final folded structure is contained within the sequence of its amino acid residues. However, the rules that dictate how a given sequence will fold into a given structure are still unclear. Understanding the rules of protein folding is of utmost importance for predicting protein structure from genomic sequence data, designing novel proteins, and understanding how and why protein folding mechanisms can fail. Failure of protein folding mechanisms, often due to genetic mutations or adverse conditions such as thermal or chemical stress, is the cause of numerous human diseases including cystic fibrosis, Alzheimer's disease, juvenile cataracts, and many forms of cancer. Research in the Clark laboratory is focused on two related topics. First, how are the rules for protein folding affected by their native environment, the cell? In the cell, proteins are synthesized in a vectorial fashion. The energy landscape for folding during chain synthesis (or secretion across a membrane) is hence quite different from the energy landscape for the folding of a full-length polypeptide chain. As a result, folding intermediates populated during refolding in vitro might be populated quite differently during vectorial folding. A particular interest in the Clark laboratory is the role of co-translational protein folding in suppressing chain misfolding and aggregation in vivo. A related interest is the display of virulence factors on the outer surface of pathogenic gram-negative bacteria. For example, these virulence proteins must fold only after secretion across two membranes; what prevents them from folding prematurely in the periplasm? Second, what are the protein folding rules that govern the formation of β-sheet structure? β-sheets represent a type of regular, repeating protein structure, characterized by an extensive hydrogen bonding network between strands of amino acid residues. Contacts between individual amino acid residues in β-sheets often represent contacts quite distant in sequence. As a result, it has been extremely difficult to define simple rules for β-sheet formation, and we expect that high contact order will make many β-sheet topologies difficult (if not impossible) to form co-translationally. We are using an extremely simple β-sheet architecture, the parallel β-helix, as a model system for developing rules for β-sheet formation.

近期论文

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Drobnak I, Braselmann E, Chaney JL, Leyton D, Bernstein HD, Lithgow T, Luirink J, Nataro JP & Clark PL (2015) Of linkers and autochaperones: An unambiguous nomenclature to identify common and uncommon themes for autotransporter secretion. Molecular Microbiology 95, 1-16. Brodsky, JL & Clark PL (2014) Protein folding in the cell: From atom to organism. FASEB Journal 28, 5034-5038. Sander IM, Chaney JL & Clark PL (2014) Expanding Anfinsen’s principle: Contributions of synonymous codon selection to rational protein design. Journal of the American Chemical Society 136, 858-861. --> See the highlight article, published in Nature Chemistry! Besingi RN, Chaney JL & Clark PL (2013) An alternative outer membrane secretion mechanism for an autotransporter protein lacking a C-terminal stable core. Molecular Microbiology 90, 1028-1045. Braselmann E, Chaney JL & Clark PL (2013) Folding the proteome. Trends in Biochemical Sciences 38, 858-861. Braselmann E & Clark PL (2012) Autotransporters: The cellular environment reshapes a folding mechanism to promote protein transport. Journal of Physical Chemistry Letters 3, 1063-1071. Renn JP, Junker M, Besingi RN, Braselmann E & Clark PL (2012) ATP-independent control of autotransporter virulence protein transport via the folding properties of the secreted protein.Chemistry & Biology 19, 287-296. Bryan AW, Starner-Kreinbrink J, Hosur R, Clark PL & Berger B (2011) Structure-based prediction reveals capping motifs inhibit β-helix aggregation. Proceedings of the National Academy of Sciences USA 108, 11099-11104. Ugrinov KG & Clark PL (2010) Co-translational folding increases GFP folding yield. Biophysical Journal 98, 1312-1320. Clarke TF IV & Clark PL (2010) Increased incidence of rare codon clusters at gene termini: Implications for function. BMC Genomics 11, 118. Junker M & Clark PL (2010) Slow formation of aggregation-resistant beta-sheet folding intermediates. Proteins: Structure, Function & Bioinformatics 78, 812-824. Junker M, Besingi RN & Clark PL (2009) Vectorial transport and folding of an autotransporter virulence protein during outer membrane secretion. Molecular Microbiology 71, 1323-1332. Clarke TF IV & Clark PL (2008) Rare codons cluster. PLoS ONE 3, e3412 doi:10.1371/journal.pone.0003412 . Evans MS, Sander IM & Clark PL (2008) Co-translational folding promotes beta-helix formation and prevents aggregation in vivo. Journal of Molecular Biology 383, 683-692. Renn JP & Clark PL (2008) A conserved stable core structure in the passenger domain beta-helix of autotransporter virulence proteins. Biopolymers 89, 420-427. Junker M, Schuster C, McDonnell AV, Sorg KE, Finn MC, Berger B & Clark PL (2006) The pertactin beta-helix folding mechanism suggests common themes for secretion and folding of autotransporter proteins. Proceedings of the National Academy of Sciences USA 103, 4918-4923. Evans MS, Ugrinov KG, Frese M & Clark PL (2005) Homogeneous stalled ribosome nascent chain complexes produced in vivo or in vitro. Nature Methods 2, 757-762. Jain M, Evans MS, King J & Clark PL (2005) Monocolonal antibody epitope mapping describes tailspike beta-helix folding and aggregation intermediates. Journal of Biological Chemistry 280, 23032-23040. Clark PL (2004) Protein folding in the cell: Reshaping the folding funnel. Trends in Biochemical Sciences 29: 527-534. Benton CB, King J & Clark PL (2002) Characterization of a trimeric intermediate on the folding pathway of an interdigitated beta-helix structure. Biochemistry 41, 5093-5103. Clark PL & King J (2001) A newly synthesized, ribosome-bound polypeptide chain adopts conformations dissimilar from early in vitro refolding intermediates. Journal of Biological Chemistry 276, 25411-25420. Raso SW, Clark PL, Haase-Pettingell C, King J & Thomas GJ (2001) Distinct cysteine sulfhydryl environments detected by analysis of Raman S-H markers of Cys->Ser mutant proteins. Journal of Molecular Biology 307, 899-911. Clark PL, Weston BF & Gierasch LM (1998) Probing the folding of a b-clam protein using single-tryptophan constructs. Folding & Design 3, 401-412. Clark PL, Liu ZP, Rizo J & Gierasch LM (1997) Cavity formation before stable hydrogen bonding in the folding of a beta-clam protein. Nature Structural Biology 4, 883-886. Clark PL, Liu ZP, Zhang J & Gierasch LM (1996) Intrinsic tryptophans of CRABPI as probes of structure and folding. Protein Science 5, 1108-1117.