Structural determinants of protein folding

The last several decades have seen an explosion of knowledge in the field of structural biology. With critical advances in spectroscopic techniques in examining structures of biomacromolecules, in maturation of molecular biology techniques, as well as vast improvements in computation prowess, protein structures are now being elucidated at an unprecedented rate. In spite of all the recent advances, the protein folding puzzle remains as one of the fundamental biochemical challenges. A facet to this empiric problem is the structural determinants of protein folding. What are the driving forces that pivot a polypeptide chain to a specific conformation amongst the vast conformation space? In this review, we shall discuss some of the structural determinants to protein folding that have been identified in the recent decades.

[1]  W. DeGrado,et al.  DESIGN, SYNTHESIS, AND CHARACTERIZATION OF A CYTOTOXIC PEPTIDE WITH MELITTIN-LIKE ACTIVITY , 1981 .

[2]  J H Miller,et al.  Genetic studies of the lac repressor. I. Correlation of mutational sites with specific amino acid residues: construction of a colinear gene-protein map. , 1977, Journal of molecular biology.

[3]  Andreas Martin,et al.  A proline switch controls folding and domain interactions in the gene-3-protein of the filamentous phage fd. , 2003, Journal of molecular biology.

[4]  H. Nagasawa,et al.  Significance of a carboxyl-terminal amide moiety in the folding and biological activity of crustacean hyperglycemic hormone , 2002, Peptides.

[5]  W. Lim,et al.  The role of internal packing interactions in determining the structure and stability of a protein. , 1991, Journal of molecular biology.

[6]  Y. Kubo,et al.  The transition state in the folding-unfolding reaction of four species of three-disulfide variant of hen lysozyme: the role of each disulfide bridge. , 2000, Journal of molecular biology.

[7]  S. Maleknia,et al.  Oxidation inhibits amyloid fibril formation of transthyretin , 2006, The FEBS journal.

[8]  H. Dyson,et al.  Three-dimensional structure of a type VI turn in a linear peptide in water solution. Evidence for stacking of aromatic rings as a major stabilizing factor. , 1994, Journal of molecular biology.

[9]  A. Lupas,et al.  The structure of alpha-helical coiled coils. , 2005, Advances in protein chemistry.

[10]  V. Muñoz,et al.  Elucidating the folding problem of helical peptides using empirical parameters. II. Helix macrodipole effects and rational modification of the helical content of natural peptides. , 1995, Journal of molecular biology.

[11]  J. Richardson,et al.  De novo design, expression, and characterization of Felix: a four-helix bundle protein of native-like sequence. , 1990, Science.

[12]  C Sander,et al.  On the use of sequence homologies to predict protein structure: identical pentapeptides can have completely different conformations. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Andreas Martin,et al.  Prolyl isomerization as a molecular timer in phage infection , 2005, Nature Structural &Molecular Biology.

[14]  Howard Hughes Medical.  Folding of Bovine Pancreatic Trypsin Inhibitor (BPTI) Variants in which Almost Half the Residues are Alanine , 2000 .

[15]  Brian Kuhlman,et al.  Design of protein conformational switches. , 2006, Current opinion in structural biology.

[16]  P. Wolynes,et al.  Conformational switching upon phosphorylation: a predictive framework based on energy landscape principles. , 2008, Biochemistry.

[17]  S. Gellman,et al.  Redox control of secondary structure in a designed peptide , 1993 .

[18]  G. Melino,et al.  Protein Unfolding by Peptidylarginine Deiminase , 1996, The Journal of Biological Chemistry.

[19]  J Li,et al.  Conformation and function of the N-linked glycan in the adhesion domain of human CD2 , 1995, Science.

[20]  M. Morcellet,et al.  Preferential and absolute adsorption to poly[N5-(3-hydroxypropyl)-L-glutamine] in water/2-chloroethanol solvent mixtures. , 1977, Macromolecules.

[21]  E. Komives,et al.  NMR structures reveal how oxidation inactivates thrombomodulin. , 2003, Biochemistry.

[22]  B. Zimm,et al.  Theory of the Phase Transition between Helix and Random Coil in Polypeptide Chains , 1959 .

[23]  Michele Vendruscolo,et al.  A PDZ domain recapitulates a unifying mechanism for protein folding , 2007, Proceedings of the National Academy of Sciences.

[24]  L. Nicholson,et al.  Prolyl cis-trans isomerization as a molecular timer. , 2007, Nature chemical biology.

[25]  J. Phillips,et al.  Locust ion transport peptide (ITP): primary structure, cDNA and expression in a baculovirus system. , 1996, The Journal of experimental biology.

[26]  Alan R. Fersht,et al.  From the first protein structures to our current knowledge of protein folding: delights and scepticisms , 2008, Nature Reviews Molecular Cell Biology.

[27]  A. Soldatova,et al.  Protein dynamics from time resolved UV Raman spectroscopy. , 2008, Current opinion in structural biology.

[28]  Anna Tramontano,et al.  Critical assessment of methods of protein structure prediction—Round VII , 2007, Proteins.

[29]  W E Stites,et al.  Packing is a key selection factor in the evolution of protein hydrophobic cores. , 2001, Biochemistry.

[30]  P. Gopalakrishnakone,et al.  lambda-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus. , 2000, The Journal of biological chemistry.

[31]  O. Ptitsyn,et al.  Physical reasons for secondary structure stability: α‐Helices in short peptides , 1991 .

[32]  L. Pedersen,et al.  Conformational Changes in Conantokin-G Induced upon Binding of Calcium and Magnesium as Revealed by NMR Structural Analysis* , 1998, The Journal of Biological Chemistry.

[33]  E. Shakhnovich,et al.  What can disulfide bonds tell us about protein energetics, function and folding: simulations and bioninformatics analysis. , 2000, Journal of molecular biology.

[34]  J. Thornton,et al.  Influence of proline residues on protein conformation. , 1991, Journal of molecular biology.

[35]  Zoran Obradovic,et al.  The Protein Non-Folding Problem: Amino Acid Determinants of Intrinsic Order and Disorder , 2000, Pacific Symposium on Biocomputing.

[36]  Valerie Daggett,et al.  Unifying features in protein-folding mechanisms , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Alessandro Borgia,et al.  Single-molecule studies of protein folding. , 2008, Annual review of biochemistry.

[38]  Michele Vendruscolo,et al.  Theoretical approaches to protein aggregation. , 2006, Protein and peptide letters.

[39]  C. Tatko,et al.  Comparison of C-H...pi and hydrophobic interactions in a beta-hairpin peptide: impact on stability and specificity. , 2004, Journal of the American Chemical Society.

[40]  W. Lim,et al.  Deciphering the message in protein sequences: tolerance to amino acid substitutions. , 1990, Science.

[41]  C. Anfinsen,et al.  Regeneration of enzyme activity by air oxidation of reduced subtilisin-modified ribonuclease. , 1961, The Journal of biological chemistry.

[42]  Lynne Regan,et al.  Construction and Design of ‚-Sheets , 1997 .

[43]  R. Sauer,et al.  Tolerance of Arc repressor to multiple-alanine substitutions. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  P. S. Kim,et al.  The C-peptide helix from ribonuclease A considered as an autonomous folding unit. , 1987, Cold Spring Harbor symposia on quantitative biology.

[45]  P. S. Kim,et al.  A helix stop signal in the isolated S-peptide of ribonuclease A , 1984, Nature.

[46]  R. Cook,et al.  Differential glycosylation requirements for the cell surface expression of class I molecules. , 1985, Journal of immunology.

[47]  Wei Yang,et al.  Rational design of a conformation‐switchable Ca2+‐ and Tb3+‐binding protein without the use of multiple coupled metal‐binding sites , 2008, The FEBS journal.

[48]  M. Brunori,et al.  Mechanisms of protein folding , 2008, European Biophysics Journal.

[49]  R. L. Baldwin,et al.  Temperature dependence of the hydrophobic interaction in protein folding. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[50]  M. Weiss,et al.  Hierarchical protein "un-design": insulin's intrachain disulfide bridge tethers a recognition alpha-helix. , 2000, Biochemistry.

[51]  W. C. Johnson,et al.  Analysis of circular dichroism spectra. , 1992, Methods in enzymology.

[52]  D. Payne.  Posttranslational Modification of Proteins by ADP-ribosylation , 1984 .

[53]  J. Howard,et al.  Isolation and characterization of vitamin K-dependent region of bovine blood clotting factor X. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[54]  A. F. Bradbury,et al.  Peptide amidation. , 1991, Trends in biochemical sciences.

[55]  O. Ptitsyn.  How molten is the molten globule? , 1996, Nature Structural Biology.

[56]  A. Fersht,et al.  Is there a unifying mechanism for protein folding? , 2003, Trends in biochemical sciences.

[57]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[58]  C. Barrow,et al.  Solution conformations and aggregational properties of synthetic amyloid beta-peptides of Alzheimer's disease. Analysis of circular dichroism spectra. , 1992, Journal of molecular biology.

[59]  J. Lucchesi,et al.  mof, a putative acetyl transferase gene related to the Tip60 and MOZ human genes and to the SAS genes of yeast, is required for dosage compensation in Drosophila , 1997, The EMBO journal.

[60]  G. Bulaj,et al.  Folding of conotoxins: formation of the native disulfide bridges during chemical synthesis and biosynthesis of Conus peptides. , 2008, Antioxidants & redox signaling.

[61]  L. McIntire,et al.  Tyrosine Sulfation of Glycoprotein Ibα , 2001, The Journal of Biological Chemistry.

[62]  G. Snyder,et al.  Factors governing selective formation of specific disulfides in synthetic variants of alpha-conotoxin. , 1991, Biochemistry.

[63]  S. Jacobs,et al.  Structure of HP1 Chromodomain Bound to a Lysine 9-Methylated Histone H3 Tail , 2002, Science.

[64]  Amedeo Caflisch,et al.  Network and graph analyses of folding free energy surfaces. , 2006, Current opinion in structural biology.

[65]  Oxidative folding of ω‐conotoxin MVIIC: Effects of temperature and salt , 1996 .

[66]  D. Baker,et al.  Design of a Novel Globular Protein Fold with Atomic-Level Accuracy , 2003, Science.

[67]  M Karplus,et al.  Protein folding dynamics: The diffusion‐collision model and experimental data , 1994, Protein science : a publication of the Protein Society.

[68]  L. Pauling,et al.  The structure of proteins; two hydrogen-bonded helical configurations of the polypeptide chain. , 1951, Proceedings of the National Academy of Sciences of the United States of America.

[69]  D F Doyle,et al.  Protein thermal denaturation, side-chain models, and evolution: amino acid substitutions at a conserved helix-helix interface. , 1995, Biochemistry.

[70]  S. Millard,et al.  Dscam-mediated cell recognition regulates neural circuit formation. , 2008, Annual Review of Cell and Developmental Biology.

[71]  C. Anfinsen,et al.  The kinetics of formation of native ribonuclease during oxidation of the reduced polypeptide chain. , 1961, Proceedings of the National Academy of Sciences of the United States of America.

[72]  D. Merkler.  C‐Terminal Amidated Peptides: Production by the in vitro Enzymic Amidation of Glycine‐Extended Peptides and the Importance of the Amide to Bioactivity , 1994 .

[73]  Gen‐jun Xu,et al.  The sequence determinant causing different folding behaviors of insulin and insulin-like growth factor-1. , 2007, Biochemistry.

[74]  Ronald T. Raines,et al.  2005 Emil Thomas Kaiser Award , 2006, Protein science : a publication of the Protein Society.

[75]  P. Chakrabarti,et al.  C--H...O hydrogen bond involving proline residues in alpha-helices. , 1998, Journal of molecular biology.

[76]  Sheena E Radford,et al.  Intermediates: ubiquitous species on folding energy landscapes? , 2007, Current opinion in structural biology.

[77]  S. Schreiber,et al.  A receptor for the immuno-suppressant FK506 is a cis–trans peptidyl-prolyl isomerase , 1989, Nature.

[78]  J. Strominger,et al.  Analysis of the oligosaccharides on the HLA-DR and DC1 B cell antigens. , 1983, Journal of immunology.

[79]  B. Matthews,et al.  The role of backbone flexibility in the accommodation of variants that repack the core of T4 lysozyme. , 1994, Science.

[80]  S. Elliott,et al.  Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. , 2005, Journal of pharmaceutical sciences.

[81]  G. Bulaj,et al.  Role of hydroxyprolines in the in vitro oxidative folding and biological activity of conotoxins. , 2008, Biochemistry.

[82]  L. Fiorucci,et al.  Protein folding, unfolding and misfolding: role played by intermediate States. , 2008, Mini reviews in medicinal chemistry.

[83]  M. Morcellet,et al.  Preferential and absolute adsorption on poly(l-glutamic acid) in water — dioxane mixtures , 1975 .

[84]  Terrence G Oas,et al.  Methionine oxidation of monomeric lambda repressor: the denatured state ensemble under nondenaturing conditions. , 2006, Protein science : a publication of the Protein Society.

[85]  D. Wetlaufer.  Nucleation, rapid folding, and globular intrachain regions in proteins. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[86]  Lynne Regan,et al.  Redesigning the hydrophobic core of a four‐helix‐bundle protein , 1994, Protein science : a publication of the Protein Society.

[87]  M. Schiffer,et al.  Use of helical wheels to represent the structures of proteins and to identify segments with helical potential. , 1967, Biophysical journal.

[88]  A. Fersht,et al.  Engineered disulfide bonds as probes of the folding pathway of barnase: increasing the stability of proteins against the rate of denaturation. , 1993, Biochemistry.

[89]  F. Knoop,et al.  Antimicrobial peptides isolated from skin secretions of the diploid frog, Xenopus tropicalis (Pipidae). , 2001, Biochimica et biophysica acta.

[90]  P. Fossier,et al.  A conotoxin from Conus textile with unusual posttranslational modifications reduces presynaptic Ca2+ influx. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[91]  J. McIntosh,et al.  Carboxyglutamate in a Neuroactive Toxin , 2022 .

[92]  B. Imperiali,et al.  Analysis of the conserved glycosylation site in the nicotinic acetylcholine receptor: potential roles in complex assembly. , 1995, Chemistry & biology.

[93]  Terrence G. Oas,et al.  Methionine oxidation of monomeric λ repressor: The denatured state ensemble under nondenaturing conditions , 2006 .

[94]  J. Lian,et al.  Direct identification of the calcium-binding amino acid, gamma-carboxyglutamate, in mineralized tissue. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[95]  D Baker,et al.  Simplified proteins: minimalist solutions to the 'protein folding problem'. , 1998, Current opinion in structural biology.

[96]  R. L. Baldwin,et al.  Helix stabilization by Glu-...Lys+ salt bridges in short peptides of de novo design. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[97]  A. Helenius,et al.  Roles of N-linked glycans in the endoplasmic reticulum. , 2004, Annual review of biochemistry.

[98]  C. Schöneich,et al.  Loss of conformational stability in calmodulin upon methionine oxidation. , 1998, Biophysical journal.

[99]  M. Waters,et al.  Arginine methylation in a beta-hairpin peptide: implications for Arg-pi interactions, DeltaCp(o), and the cold denatured state. , 2006, Journal of the American Chemical Society.

[100]  Zhan-Yun Guo,et al.  The in vitro oxidative folding of the insulin superfamily. , 2008, Antioxidants & redox signaling.

[101]  L. Regan,et al.  Construction and Design of β-Sheets , 1997 .

[102]  Tanja Kortemme,et al.  Design of a 20-Amino Acid, Three-Stranded β-Sheet Protein , 1998 .

[103]  S Walter Englander,et al.  Protein folding and misfolding: mechanism and principles , 2007, Quarterly Reviews of Biophysics.

[104]  L. H. Bradley,et al.  Protein design by binary patterning of polar and nonpolar amino acids. , 1993, Methods in molecular biology.

[105]  A. Lesk,et al.  Determinants of a protein fold. Unique features of the globin amino acid sequences. , 1987, Journal of molecular biology.

[106]  M Karplus,et al.  The Levinthal paradox: yesterday and today. , 1997, Folding & design.

[107]  Pinak Chakrabarti,et al.  C—H⋯O hydrogen bond involving proline residues in α-helices , 1998 .

[108]  P. Y. Chou,et al.  Empirical predictions of protein conformation. , 1978, Annual review of biochemistry.

[109]  B. Oostra,et al.  Human lysosomal alpha-glucosidase: functional characterization of the glycosylation sites. , 1993, The Biochemical journal.

[110]  M. Hecht,et al.  De novo proteins from combinatorial libraries. , 2001, Chemical reviews.

[111]  T. Creighton,et al.  Protein Folding: An unfolding story , 1995, Current Biology.

[112]  K. Dill.  Dominant forces in protein folding. , 1990, Biochemistry.

[113]  M. Oliveberg,et al.  Malleability of protein folding pathways: a simple reason for complex behaviour. , 2007, Current opinion in structural biology.

[114]  Jane Clarke,et al.  Mechanical unfolding of proteins: insights into biology, structure and folding. , 2007, Current opinion in structural biology.

[115]  Kai Griebenow,et al.  Effects of glycosylation on the stability of protein pharmaceuticals. , 2009, Journal of pharmaceutical sciences.

[116]  C. Kannicht.  Posttranslational Modification of Proteins , 2002 .

[117]  L Serrano,et al.  Design of a 20-amino acid, three-stranded beta-sheet protein. , 1998, Science.

[118]  H. Scheraga,et al.  Helix‐coil stability constants for the naturally occurring amino acids in water. XXIII. Proline parameters from random poly(hydroxybutylglutamine‐CO‐L‐proline) , 1990, Biopolymers.

[119]  H. Scheraga,et al.  Helix‐coil stability constants for the naturally occurring amino acids in water. XII. Asparagine parameters from random poly(hydroxybutylglutamine‐co‐L‐asparagine) , 1977, Biopolymers.

[120]  H. Scheraga,et al.  The influence of short-range interactions on protein onformation. II. A model for predicting the alpha-helical regions of proteins. , 1969, Proceedings of the National Academy of Sciences of the United States of America.

[121]  W. DeGrado,et al.  Protein-protein interactions in the membrane: sequence, structural, and biological motifs. , 2008, Structure.

[122]  J. Miller,et al.  Genetic studies of the lac repressor. X. Analysis of missense mutations in the lacI gene. , 1979, Journal of molecular biology.

[123]  Vladimir N Uversky,et al.  Amyloidogenesis of natively unfolded proteins. , 2008, Current Alzheimer research.

[124]  A. Fersht.  Nucleation mechanisms in protein folding. , 1997, Current opinion in structural biology.

[125]  M. Shearer.  Vitamin K metabolism and nutriture. , 1992, Blood reviews.

[126]  M. Karplus,et al.  How does a protein fold? , 1994, Nature.

[127]  R. L. Baldwin,et al.  The search for folding intermediates and the mechanism of protein folding. , 2008, Annual review of biophysics.

[128]  R. Kini,et al.  Effect of C-Terminal Amidation on Folding and Disulfide-Pairing of α-Conotoxin ImI† , 2005 .

[129]  C. Anfinsen.  Principles that govern the folding of protein chains. , 1973, Science.

[130]  Hajime Nakamura,et al.  Thioredoxin and its related molecules: update 2005. , 2005, Antioxidants & redox signaling.

[131]  Wei R. Chen,et al.  The Number and Location of Glycans on Influenza Hemagglutinin Determine Folding and Association with Calnexin and Calreticulin , 1997, The Journal of cell biology.

[132]  R. Goody,et al.  Farnesylation of the SNARE protein Ykt6 increases its stability and helical folding. , 2008, Journal of molecular biology.

[133]  Nikolay V Dokholyan,et al.  Studies of folding and misfolding using simplified models. , 2006, Current opinion in structural biology.

[134]  T. Hayano,et al.  Peptidyl-prolyl cis-trans isomerase is the cyclosporin A-binding protein cyclophilin , 1989, Nature.

[135]  S. Hober,et al.  Disulfide exchange folding of insulin-like growth factor I. , 1992, Biochemistry.

[136]  R. L. Baldwin,et al.  Large differences in the helix propensities of alanine and glycine , 1991, Nature.

[137]  Mohammad M. Islam,et al.  Crystal structure of an extensively simplified variant of bovine pancreatic trypsin inhibitor in which over one-third of the residues are alanines , 2008, Proceedings of the National Academy of Sciences.

[138]  L Serrano,et al.  Elucidating the folding problem of helical peptides using empirical parameters. III. Temperature and pH dependence. , 1995, Journal of molecular biology.

[139]  B Yasin,et al.  Protegrins: structural requirements for inactivating elementary bodies of Chlamydia trachomatis , 1996, Infection and immunity.

[140]  T. Creighton.  Proteins: Structures and Molecular Properties , 1986 .

[141]  Y. Levy,et al.  Effect of glycosylation on protein folding: A close look at thermodynamic stabilization , 2008, Proceedings of the National Academy of Sciences.

[142]  R Dustin Schaeffer,et al.  Combining experiment and simulation in protein folding: closing the gap for small model systems. , 2008, Current opinion in structural biology.

[143]  J H Miller,et al.  Genetic studies of the lac repressor. IX. Generation of altered proteins by the suppression of nonsence mutations. , 1979, Journal of molecular biology.

[144]  T. Creighton,et al.  Protein Folding , 1992 .

[145]  P. S. Kim,et al.  Specific intermediates in the folding reactions of small proteins and the mechanism of protein folding. , 1982, Annual review of biochemistry.

[146]  J. Neyton,et al.  Consequence of the removal of evolutionary conserved disulfide bridges on the structure and function of charybdotoxin and evidence that particular cysteine spacings govern specific disulfide bond formation. , 1998, Biochemistry.

[147]  R Fine,et al.  FASTRUN: A special purpose, hardwired computer for molecular simulation , 1991, Proteins.

[148]  G. Wagner,et al.  The structural role of sugars in glycoproteins. , 1996, Current opinion in biotechnology.

[149]  Donald Hilvert,et al.  An Active Enzyme Constructed from a 9-Amino Acid Alphabet* , 2005, Journal of Biological Chemistry.

[150]  E. Komives,et al.  The fifth epidermal growth factor-like domain of thrombomodulin does not have an epidermal growth factor-like disulfide bonding pattern. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[151]  D. Bozon,et al.  IDS transfer from overexpressing cells to IDS-deficient cells. , 1997, Experimental cell research.

[152]  W. DeGrado,et al.  DESIGN, SYNTHESIS, AND CHARACTERIZATION OF A CYTOTOXIC PEPTIDE WITH MELITTIN-LIKE ACTIVITY , 1981 .

[153]  M. Waters,et al.  Arginine methylation in a β-hairpin peptide: Implications for Arg-π interactions, ΔCp°, and the cold denatured state , 2006 .

[154]  B. Honig.  Protein folding: from the levinthal paradox to structure prediction. , 1999, Journal of molecular biology.

[155]  B. Matthews,et al.  Response of a protein structure to cavity-creating mutations and its relation to the hydrophobic effect. , 1992, Science.

[156]  C. Chothia,et al.  Helix to helix packing in proteins. , 1981, Journal of molecular biology.

[157]  R. Berry,et al.  Nitration in neurodegeneration: deciphering the "Hows" "nYs". , 2007, Biochemistry.

[158]  Donald Hilvert,et al.  Searching sequence space for protein catalysts , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[159]  D. Turk,et al.  Essential role of proline isomerization in stefin B tetramer formation. , 2007, Journal of molecular biology.

[160]  Adding backbone to protein folding: why proteins are polypeptides. , 1995, Folding & design.

[161]  R. Woody,et al.  Identification of proline residues responsible for the slow folding kinetics in pectate lyase C by mutagenesis. , 2002, Biochemistry.

[162]  A. Tanaka.  [A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase]. , 2007, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[163]  S. Oyama,et al.  How C-terminal carboxyamidation alters the biological activity of peptides from the venom of the eumenine solitary wasp. , 2004, Biochemistry.

[164]  Peter E Wright,et al.  Elucidation of the protein folding landscape by NMR. , 2005, Methods in enzymology.

[165]  D. Shortle,et al.  Persistence of Native-Like Topology in a Denatured Protein in 8 M Urea , 2001, Science.

[166]  R. Desnick,et al.  Human alpha-galactosidase A: glycosylation site 3 is essential for enzyme solubility. , 1998, The Biochemical journal.

[167]  E. Carlier,et al.  Disulfide bridge reorganization induced by proline mutations in maurotoxin , 2001, FEBS letters.

[168]  C. Sevier,et al.  Formation and transfer of disulphide bonds in living cells , 2002, Nature Reviews Molecular Cell Biology.

[169]  L. Baltzer,et al.  De Novo Design of Proteins — What Are the Rules? , 2010 .

[170]  R. Brady.  Enzyme replacement for lysosomal diseases. , 2006, Annual review of medicine.

[171]  K. Faull,et al.  Carbohydrate Structures of Recombinant Human α-l-Iduronidase Secreted by Chinese Hamster Ovary Cells* , 1997, The Journal of Biological Chemistry.

[172]  G. Bulaj,et al.  Efficient oxidative folding of conotoxins and the radiation of venomous cone snails , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[173]  G. Dockray,et al.  Biological activity of carboxy-terminal gastrin analogs. , 1999, European journal of pharmacology.

[174]  R. Brossmer,et al.  Effect of the carbohydrate moiety on the secondary structure of beta 2-glycoprotein. I. Implications for the biosynthesis and folding of glycoproteins. , 1990, Biochemistry.

[175]  S. Kornfeld.  Trafficking of lysosomal enzymes in normal and disease states. , 1986, The Journal of clinical investigation.

[176]  J. Miller.  Genetic studies of the lac repressor. XI. On aspects of lac repressor structure suggested by genetic experiments. , 1979, Journal of molecular biology.

[177]  C. Levinthal.  How to fold graciously , 1969 .

[178]  P. Conn,et al.  G Protein-Coupled Receptor Trafficking in Health and Disease: Lessons Learned to Prepare for Therapeutic Mutant Rescue in Vivo , 2007, Pharmacological Reviews.

[179]  J. Thornton.  Disulphide bridges in globular proteins. , 1981, Journal of molecular biology.

[180]  Jeffrey Skolnick,et al.  All-atom ab initio folding of a diverse set of proteins. , 2006, Structure.

[181]  M. Brunori,et al.  Identification and characterization of protein folding intermediates. , 2007, Biophysical chemistry.

[182]  J. Sussman,et al.  human acid-beta-glucosidase , 2003 .

[183]  B. Imperiali,et al.  Modulation of protein structure and function by asparagine-linked glycosylation. , 1996, Chemistry & biology.

[184]  C. Scriver,et al.  The Metabolic and Molecular Bases of Inherited Disease, 8th Edition 2001 , 2001, Journal of Inherited Metabolic Disease.

[185]  C. Pace,et al.  Contribution of hydrophobic interactions to protein stability. , 2011, Journal of molecular biology.

[186]  B. Matthews,et al.  A test of the "jigsaw puzzle" model for protein folding by multiple methionine substitutions within the core of T4 lysozyme. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[187]  L. Johnson,et al.  Structural Basis for Control by Phosphorylation , 2001 .

[188]  A. Mor,et al.  The NH2-terminal alpha-helical domain 1-18 of dermaseptin is responsible for antimicrobial activity. , 1994, The Journal of biological chemistry.

[189]  J. Richardson,et al.  The tyrosine corner: A feature of most greek key β‐barrel proteins , 1994 .

[190]  L. Ruddock,et al.  Three Binding Sites in Protein-disulfide Isomerase Cooperate in Collagen Prolyl 4-Hydroxylase Tetramer Assembly* , 2005, Journal of Biological Chemistry.

[191]  Loïc Martin,et al.  Role of disulfide bonds in folding and activity of leiurotoxin I: just two disulfides suffice. , 2002, Biochemistry.

[192]  T. Kiefhaber,et al.  Evidence for sequential barriers and obligatory intermediates in apparent two-state protein folding. , 2003, Journal of molecular biology.

[193]  K. Honke,et al.  Components and proteolytic processing sites of arylsulfatase B from human placenta. , 1992, Biochimica et biophysica acta.

[194]  M. Waters,et al.  Influence of N-methylation on a cation-π interaction produces a remarkably stable β-hairpin peptide , 2005 .

[195]  J. Miller,et al.  Role of native disulfide bonds in the structure and activity of insulin-like growth factor 1: genetic models of protein-folding intermediates. , 1993, Biochemistry.

[196]  K. Dill,et al.  The Protein Folding Problem , 1993 .

[197]  A. Fersht.  Optimization of rates of protein folding: the nucleation-condensation mechanism and its implications. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[198]  Alan R Davidson,et al.  The structure of “unstructured” regions in peptides and proteins: Role of the polyproline II helix in protein folding and recognition * , 2005, Biopolymers.

[199]  D C Richardson,et al.  The tyrosine corner: a feature of most Greek key beta-barrel proteins. , 1994, Protein science : a publication of the Protein Society.

[200]  A. Mirsky,et al.  On the Structure of Native, Denatured, and Coagulated Proteins. , 1936, Proceedings of the National Academy of Sciences of the United States of America.

[201]  Andrei N. Lupas,et al.  The structure of α-helical coiled coils , 2005 .

[202]  Luis Serrano,et al.  Elucidating the folding problem of helical peptides using empirical parameters , 1994, Nature Structural Biology.

[203]  Y. Ioannou,et al.  Human acid beta-glucosidase. N-glycosylation site occupancy and the effect of glycosylation on enzymatic activity. , 1993, The Journal of biological chemistry.

[204]  J. Mayer,et al.  The Folding Nucleus of the Insulin Superfamily , 2006, Journal of Biological Chemistry.

[205]  R. L. Baldwin,et al.  Unusually stable helix formation in short alanine-based peptides. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[206]  Stefan M. Larson,et al.  The family feud: do proteins with similar structures fold via the same pathway? , 2005, Current opinion in structural biology.

[207]  T. Ooi,et al.  Comparison of α‐helix stability in peptides having a negatively or positively charged residue block attached either to the N‐ or C‐terminus of an α‐helix: The electrostatic contribution and anisotropic stability of the α‐helix , 1989 .

[208]  L. Regan,et al.  Combinatorial approaches to protein stability and structure. , 2004, European journal of biochemistry.

[209]  Marcey L. Waters,et al.  Comparison of C−H···π and Hydrophobic Interactions in a β-Hairpin Peptide: Impact on Stability and Specificity , 2004 .

[210]  F M Richards,et al.  An analysis of packing in the protein folding problem , 1993, Quarterly Reviews of Biophysics.

[211]  Chi-Huey Wong,et al.  Protein glycosylation: new challenges and opportunities. , 2005, The Journal of organic chemistry.

[212]  A. Fersht,et al.  Active barnase variants with completely random hydrophobic cores. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[213]  J W Suttie.  Vitamin K-dependent carboxylase. , 1985, Annual review of biochemistry.

[214]  D. Baker,et al.  Functional rapidly folding proteins from simplified amino acid sequences , 1997, Nature Structural Biology.

[215]  T. MacRae.  Tubulin post-translational modifications--enzymes and their mechanisms of action. , 1997, European journal of biochemistry.

[216]  H. Dyson,et al.  Unfolded proteins and protein folding studied by NMR. , 2004, Chemical reviews.

[217]  M. Waters,et al.  Influence of N-methylation on a cation-pi interaction produces a remarkably stable beta-hairpin peptide. , 2005, Journal of the American Chemical Society.

[218]  J. Hofrichter,et al.  The protein folding 'speed limit'. , 2004, Current opinion in structural biology.

[219]  G. Bulaj,et al.  Conotoxins and the posttranslational modification of secreted gene products , 2005, Cellular and Molecular Life Sciences CMLS.

[220]  G. Bulaj,et al.  Conantokin-P, an unusual conantokin with a long disulfide loop. , 2008, Toxicon : official journal of the International Society on Toxinology.

[221]  A. Fersht,et al.  The folding of an enzyme. I. Theory of protein engineering analysis of stability and pathway of protein folding. , 1992, Journal of molecular biology.

[222]  P. S. Kim,et al.  A switch between two-, three-, and four-stranded coiled coils in GCN4 leucine zipper mutants. , 1993, Science.

[223]  Robert M. Hughes,et al.  Effects of Lysine Acetylation in a β-Hairpin Peptide: Comparison of an Amide−π and a Cation−π Interaction , 2006 .

[224]  L. Longo,et al.  A logical OR redundancy within the Asx-Pro-Asx-Gly type I beta-turn motif. , 2008, Journal of molecular biology.

[225]  Linus Pauling,et al.  The Structure of Proteins , 1939 .

[226]  R. Kini,et al.  Molecular moulds with multiple missions: Functional sites in three‐finger toxins , 2002, Clinical and experimental pharmacology & physiology.

[227]  A. Drake,et al.  The importance of extended conformations and, in particular, the PII conformation for the molecular recognition of peptides , 1995, Biopolymers.

[228]  Alessandro Senes,et al.  Folding of helical membrane proteins: the role of polar, GxxxG-like and proline motifs. , 2004, Current opinion in structural biology.

[229]  Hang-Cheol Shin,et al.  Role of disulfide bonds in the structure and activity of human insulin. , 2003, Molecules and cells.

[230]  Robert M. Stroud,et al.  A designed four helix bundle protein with native-like structure , 1997, Nature Structural Biology.

[231]  J. Thornton,et al.  Helix geometry in proteins. , 1988, Journal of molecular biology.

[232]  N. Sharon,et al.  Structure of a legume lectin with an ordered N-linked carbohydrate in complex with lactose. , 1991, Science.

[233]  M. Searle,et al.  Aromatic residues engineered into the beta-turn nucleation site of ubiquitin lead to a complex folding landscape, non-native side-chain interactions, and kinetic traps. , 2008, Biochemistry.

[234]  O. Ptitsyn,et al.  How the molten globule became. , 1995, Trends in biochemical sciences.

[235]  D. Merkler,et al.  C-terminal amidated peptides: production by the in vitro enzymatic amidation of glycine-extended peptides and the importance of the amide to bioactivity. , 1994, Enzyme and microbial technology.

[236]  A. Finkelstein,et al.  Physical reasons for secondary structure stability: alpha-helices in short peptides. , 1991, Proteins.

[237]  J. W. Wong,et al.  Allosteric Disulfide Bonds , 2006 .

[238]  R. Dwek,et al.  Glycoproteins: glycan presentation and protein-fold stability. , 1999, Structure.

[239]  P. Taylor,et al.  Protein folding determinants: structural features determining alternative disulfide pairing in alpha- and chi/lambda-conotoxins. , 2007, Biochemistry.

[240]  M. Marín,et al.  Folding at the rhythm of the rare codon beat , 2008, Biotechnology journal.

[241]  J. Onuchic,et al.  Protein folding funnels: a kinetic approach to the sequence-structure relationship. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[242]  C. Janke,et al.  Polyglutamylation: a fine‐regulator of protein function? , 2008, EMBO reports.

[243]  A Helenius,et al.  How N-linked oligosaccharides affect glycoprotein folding in the endoplasmic reticulum. , 1994, Molecular biology of the cell.

[244]  V. Uversky,et al.  Conformational constraints for amyloid fibrillation: the importance of being unfolded. , 2004, Biochimica et biophysica acta.

[245]  S. L. Mayo,et al.  De novo protein design: fully automated sequence selection. , 1997, Science.

[246]  J. McIntosh,et al.  Gamma-carboxyglutamate in a neuroactive toxin. , 1984, The Journal of biological chemistry.

[247]  T. Creighton.  Disulfide bonds as probes of protein folding pathways. , 1986, Methods in enzymology.

[248]  J. Ramshaw,et al.  The collagen triple-helix structure. , 1997, Matrix biology : journal of the International Society for Matrix Biology.

[249]  S. Kornfeld,et al.  Effect of tunicamycin on IgM, IgA, and IgG secretion by mouse plasmacytoma cells. , 1978, Journal of immunology.

[250]  B. Kemper,et al.  Structural basis for the role in protein folding of conserved proline-rich regions in cytochromes P450. , 2004, Toxicology and applied pharmacology.

[251]  G. Bulaj,et al.  Oxidative folding of conotoxins sharing an identical disulfide bridging framework , 2005, The FEBS journal.

[252]  D. Raleigh,et al.  Electrostatic interactions in the denatured state and in the transition state for protein folding: effects of denatured state interactions on the analysis of transition state structure. , 2006, Journal of molecular biology.

[253]  D. Lomas,et al.  Conformational disease , 1997, The Lancet.

[254]  S. Teichmann,et al.  The folding and evolution of multidomain proteins , 2007, Nature Reviews Molecular Cell Biology.

[255]  R. Raines,et al.  Stabilization of the collagen triple helix by O-methylation of hydroxyproline residues. , 2008, Journal of the American Chemical Society.

[256]  C. Waldburger,et al.  Sequence determinants of folding and stability for the P22 Arc repressor dimer , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[257]  Marcey L. Waters,et al.  Aromatic interactions in peptides: Impact on structure and function , 2004, Biopolymers.

[258]  Robert Preissner,et al.  Conservation of cis prolyl bonds in proteins during evolution , 2004, Proteins.

[259]  A. Treston,et al.  Where does amidation take place? , 1996, Molecular and Cellular Endocrinology.

[260]  P. Y. Chou,et al.  Prediction of protein conformation. , 1974, Biochemistry.

[261]  C. Levinthal.  Are there pathways for protein folding , 1968 .

[262]  Gary Walsh,et al.  Post-translational modifications in the context of therapeutic proteins , 2006, Nature Biotechnology.