| PROJECT # | TOPICS | DESCRIPTION & CITATIONS |
|---|---|---|
| Protein folding in vitro / protein structure and sequences | ||
| 1 | The conformations of aromatic side chains in globular proteins | Most aromatic rings are found in the interior of proteins. What kinds of interactions are aromatic rings involved in within protein interiors? There is evidence in some proteins that the rings can flip. How rapidly? How general is this motion? Burley, S. K., and G. A. Petsko. "Aromatic-aromatic Interaction: Mechanism of Protein Structure Stabilization." Science 229 (1985): 23-8. ———. "Weakly Polar Interactions in Proteins." Advances in Protein Chemistry 39 (1988). Flocco, M., and S. Mowbray. "Planar Stacking Interactions of Arginine and Aromatic Side Chains in Proteins." J Mol Bio 235 (1994): 709-717. Hunter, C. A., J. Singh, and J. M. Thornton. "Pi-Pi Interactions: The Geometry and Energetics of Phenylalanine-phenylalanine Interactions in Proteins." J Mol Biol 218, no. 4 (1991): 837-46. Levitt, M., and M. F. Perutz. "Aromatic Rings Act as Hydrogen Bond Acceptors." J Mol Biol 201, no. 4 (1988): 751-4. Mitchell, J. B. O., C. L. Nandi, I. K. McDonald, J. M. Thornton, and S. L. Price. "Amino/aromatic Interactions in Proteins: Is the Evidence Stacked Against Hydrogen Bonding?" J Mol Bio 239 (1994): 315-331. Nall, B. T., and E. H. Zuniga. "Rate and Energetics of Tyrosine Ring Flips in Yeast Iso-2-cytochrome c." Biochemistry 29 (1990): 7576-7584. Serrano, L., and A. Fersht. "Aromatic-Aromatic Interactions and Protein Stability." J Mol Bio 218 (1991): 465-475. |
| 2 | The in vitro refolding of collagen | Short tripeptides with collagen-like sequences have recently been crystallized and their structure solved by X-ray diffraction. Using 2-D NMR it has been possible to follow the actual kinetics of the chain folding and association reaction and the effects of certain glycine substitutions. Baum, J., and B. Brodsky. "Real-time NMR Investigations of Triple-Helix Folding and Collagen Folding Diseases." Folding and Design 2 (1997): R53-RR60. Bhate, M., X. Wang, J. Baum, and B. Brodsky. "Folding and Conformational Consequences of Glycine to Alanine Replacements at Different Positions in a Collagen Model Peptide." Biochemistry 41, no. 20 (2002): 6539-6547. Fan, P., M. Li, B. Brodsky, and J. Baum. "Backbone Dynamics of (Pro-Hyp-Gly)10 and a Designed Collagen-like Triple-Helical Peptide by 15N NMR Relaxation and Hydrogen-Exchange Measurements." Biochemistry 32, no. 48 (1993): 13299-13309. |
| 3 | Two stranded, three stranded, four stranded coiled coils | Coiled coils are not limited to pairs; depending on the details of the residues at the buried hydrophobic positions, the helices will form trimeric and higher associations. Recent studies reveal the fine points of the relationship between sequence and tertieary associations. Harbury, P. B., T. Zhang, P. S. Kim, and T. Alber. "A Switch Between Two-, Three-, and Four-stranded Coiled Coils in GCN4 Leucine Zipper Mutants." Science 262 (1993): 1401-1407. Harbury, P. B., P. S. Kim, and T. Alber. "Crystal Structure of an Isoleucine-zipper Trimer." Nature 371 (1994): 80-83. Lovejoy, B., S. Choe, D. Cascio, D. K. McRorie, W. F. DeGrado, and D. Eisenberg. "Crystal Structure of a Synthetic Triple-stranded Alpha-helical Bundle." Science 259 (1993): 1288-1293. Malashkevich, V. N., R. A. Kammerer, V. P. Efimov, T. Schulthess, and J. Engel. "The Crystal Structure of a Five-stranded Coiled Coil in COMP: A Prototype Ion Channel?" Science 274 (1996): 761-765. Moitra, J., L. Szilak, D. Krylov, and C. Vinson. "Leucine is the Most Stabilizing Aliphatic Amino Acid in the d Position of a Dimeric Leucine Zipper Coiled Coil." Biochemistry 36 (1997): 12567-12573. |
| 4 | Electrostatic interations in the folding, association and registration of the coiled coils | Though the hydrophobic interactions are critical, charged side chains interactions also control the structure and association of coiled/coils in both tropomyosin, and leucine zippers. Recent papers report differing values for the contributions of these ion pairs to stability. Fairman, et al. "Design of Hetero-tetrameric Coiled Coils: Evidence for Increased Stabilization by Glu-Lys Ion Pair Interactions." Biochemistry 35 (1996): 2824-2829. Lavigne, et al. "Interhelical Salt Bridges, Coiled-coil Stability, and Specificity of Dimerization." Science 271 (1996): 1136-1137. Lumb, Kevin, and P. S. Kim. "Measurement of Interhelical Electrostatic Interactions in the GCN4 Leucine Zipper." Science 268 (1995): 436-439. ———. "Response: Interhelical Salt Bridges, Coiled-coil Stability, and Specificity of Dimerization." Science 271 (1996): 1137-1138. Yu, et al. "Ion Pairs Significantly Stabilize Coiled-coils in the Absence of Electrolyte." J Mol Biol 255 (1996): 367-372. |
| 5 | Helical extension and termination signals in globular proteins | Analysis of sequences at the ends of helical regions reveal preferred residues. In both Barnase and T4 lysozyme substitutions have been generated which alter the termini of helices in the proteins. Aurora, R., G. D. Rose. "Helix Capping." Protein Science 7 (1998):21-38. Bell, J. A., W. J. Becktel, U. Sauer, W. A. Baase, and B. W. Matthews. "Dissection of Helix Capping in T4 Lysozyme by Structural and Thermodynamic Analysis of Six Amino Acid Substitutions at Thr 59." Biochemistry 31 (1992): 3590-3596. Blaber, M., X. J. Zhang, J. D. Lindstrom, S. D. Pepiot, W. A. Baase, and B. W. Matthews. "Determination of Alpha-helix Propensity within the Context of a Folded Protein." J Mol Biol 235 (1994): 600-624. Buckle, A. M., P. Cramer, and A. R. Fersht. "Structural and Energetic Responses to Cavity-Creating Mutations in Hydrophobic Cores: Observation of a Buried Water Molecule and the Hydrophilic Nature of Such Hydrophobic Cavities." Biochemistry 35 (1996): 4298-4305. Chen, Y. W., and A. R. Fersht. "Stability and Salvation of Thr/Ser to Ala and Gly Mutations at the N-cap of Alpha-helices." FEBS Letters 347 (1994): 304-309. Harper, E. T., and G. D. Rose. "Helix Stop Signals in Proteins and Peptides: The Capping box." Biochemistry 32 (1993): 7605-7609. Penel, S., R. G. Morrison, R. J. Mortishire-Smith, and A. J. Doig. "Periodicity in α-Helix Lengths and C-Capping Preferences." J Mol Biol 293 (1999): 1211-1219. Presta, L. G., and G. D. Rose. "Helix Signals in Proteins." Science 240 (1988): 1632-1641; Richardson, J. S., and D. C. Richardson. "Amino Acid Preferences for Specific Locations at the Ends of Alpha-helices." Science 240 (1988): 1648-1652. Sagerman, M., L. G. Martensson, W. A. Baase, and B. W. Matthews. "A Test of Proposed Rules for Helix Capping: Implications for Protein Design." Prot Sci 11 (2002): 516-521. Seale, J. W., R. Srinivasan, and G. D. Rose. "Sequence Determinants of the Capping Box, a Stabilizing Motif at the N-termini of Alpha-helices." Protein Science 3 (1994): 1741-1745. Zhang, X. J., W. A. Baase, and B. W. Matthews. "A Helix Initiation Signal in T4 Lysozyme Identified by Polyalanine Mutagenesis." Biophys Chem 101 (2002): 43-56. |
| 6 | The refolding pathway for apomyoglobin | Hydrogen exchange and NMR have been used to identify intermediates in the refolding of apomyoglobin. This allows interpretation of a variety of human hemoglobin mutants and other sequence data. Barrick, D., and R. L. Baldwin. "Three-state Analysis of Sperm Whale Apomyoglobin Folding." Biochemistry 32 (1993): 3790. Jamin, M., and R. L. Baldwin. "Refolding and Unfolding Kinetics of the Equilibrium Folding Intermediate of Apomyoglobin." Nature Struct Biol 3 (1996): 613. Kay, M. S., et al. "Specificity of Native-like Interhelical Hydrophobic Contacts in Theapomyoglobin Intermediate." PNAS 96 (1999): 2007. Cavagnero, et al. "Effect of H Helix Destabilizing Mutations on the Kinetic and Equilibrium Folding of Apomyoglobin." J Mol Biol 285 (1999): 269. Hughson, F. M., P. E. Wright, and R. L. Baldwin. "Structural Characterization of a Partially Folded Apomyoglobin Intermediate." Science 249 (1990): 1544. |
| 7 | Circularly permuted polypeptide chains | How important is the continuity and connectedness of amino acid sequences? In BPTI, the Greek key beta barrel proteins and some larger enzymes, the N- and C- termini have been joined together and new physical ends created, to examine the effects of sequence permutation on chain folding. Goldenberg, D. P., and T. E. Creighton. "Circular and Circularly Permuted Forms of Bovine Pancreatic Trypsin Inhibitor." J Mol Biol 165 (1983): 407-413. Goldenberg, D. P. "Folding Pathway of a Circular Form of Bovine Pancreatic Trypsin Inhibitor." J Mol Biol 179 (1984): 527-545. Heinemann, U., and M. Hahn. "Circular Permutation of Polypeptide Chains: Implications for Protein Folding and Stability." Prog Biophys Molec Biol 64, no. 2 (1995): 121-143. Hennecke, J., P. Sebbel, and R. Glockshuber. "Random Circular Permutation of DsbA Reveals Segments that are Essential for Protein Folding and Stability." J Mol Biol 286 (1999): 1197-1215. Luger, K., U. Hommel, M. Herold, J. Hofsteenge, and K. Kirschner. "Correct Folding of Circularly Permuted Variants of a Ba Barrel Enzyme in vivo." Science 243 (1989): 206-210. Topell, S., J. Hennecke, and R. Glockshuber. "Circularly Permuted Variants of the Green Fluorescent Protein." FEBS Letters 457 (1999): 283-289. |
| 8 | Folding of beta sheet proteins | Recent studies have begun to identify intermediates in the formation of small beta sheet proteins such as the interleukins and fatty acid binding proteins. These experiments utilize both hygrogen/deuterium exchange combined with spectroscopic procedures. Reader, J. S., N. A. Van Nuland, G. S. Thompson, S. J. Ferguson, C. M. Dobson, and S. E. Radford. "A Partially Folded Intermediate Species of the Beta-sheet Protein Apo-pseudoazurin is Trapped During Proline Limited Folding." Protein Sci 10 (2001): 1216-1224. |
| 9 | Coupling of folding and subunit interaction in Luciferase | In many oligomeric proteins assembly proceeds not from native subunits but from folding intermediates of the subunits. One of the best understood cases is the heterdimeric luciferase from the bacteria that illuminate the eyes of deep sea fish. Baldwin, T., M. Ziegler, A. Chaffotte, and M. Goldberg. "Contribution of Folding Steps Involving the Individual Subunits of Bacterial Luciferase to the Assembly of the Active Heterodimeric Enzyme." J Biol Chem 268 (1993): 10766-10772. Baldwin, T., J. Christopher, F. Raushel, J. Sinclair, M. Ziegler, A. Fisher, and I. Rayment. "Structure of Bacterial Luciferase." Current Opinion in Struc Biol 5 (1995): 798- 809. Clark, A., J. Sinclair, and T. Baldwin. "Folding of Bacterial Luciferase Involves a Non-native Heterodimeric Intermediate in Equilibrium with the Native Enzyme and the Unfolded Subunits." J Biol Chem 268 (1993): 10773-10779. Flynn, G., C. Beckers, W. Baase, and F. Dahlquist. "Individual Subunits of Bacterial Luciferase are Molten Globules and Interact with Molecular Chaperones." PNAS 90 (1993): 10826-10830. Noland, B., and T. Baldwin. "Demonstration of Two Independently Folding Domains in the Alpha Subunit of Bacterial Luciferase by Preferential Ligand Binding-Induced Stabilization." Biochemistry 41 (2003): 3105-3112. |
| 10 | Folding and insertion of bacteriorhodopsin | One of the very few membrane proteins whose three dimensional structure has been solved is the rhodopsin of the visual system. The best defined experiments on how these transmembrane helices associate within the membrane have been done with the bacterial and mammalin opsin. Booth, Paula J. "Unraveling the Folding of Bacteriorhodopsin." Biochimica et Biophysica Acta 1460 (2000): 4-14. Lu, Hui, and Paula J. Booth. "The Final Stages of Folding of the Membrane Protein Bacteriorhodopsin Occur by Kinetically Indistinguishable Parallel Folding Paths that are Mediated by pH." Journal of Molecular Biology 299 (2000): 233-243. Huang, Kuo-Sen, Hagan Bayley, Mei-June Liao, Erwin London, and H. Gobind Khorana. "Refolding of an Integral Membrane Protein." J Biol Chem 256 (1981): 3802-3809. |
| 11 | Folding and assembly of bacterial porins | The porins are a class of membrane proteins making large pores which use large beta barrels rather than alpha helical proteins and whose 3-D structures have been solved. Kleinschmidt, et al. Biochemstry 38 (1999): 5006-5016; Kleinschmidt, and Tamm. Biochemistry 35 (1996): 12993-13000. Klose, et al. J Biol Chem 268 (1993): 25664-25670; Eppens, et al. EMBO J 16 (1997): 4295-4301; Surrey, et al. Biochemistry 35 (1996): 2283-2288. |
| Cellular apparatus | ||
| 12 | Trigger factor and DNA K; The conformations of nascent chains emerging the ribosome | What is the conformation of the newly synthesized polypeptide chain as it exits the ribosome? Does the ribosome play a role in early stages of protein folding? What are the roles of Trigger Factor? Crooke, Elliott, and Wickner, William. "Trigger Factor: A Soluble Protein that Folds pro-OmpA into a Membrane-assembly-competent Form." PNAS 84 (1987): 5216-5220. Hesterkamp, T., S. Hauser, H. Lutcke, and B. Bukau. "Escherichia Coli Trigger Factor is a Prolyl Isomerase that Associates with Nascent Polypeptide Chains." PNAS 93 (1996): 4437-4441. Hesterkamp, T., E. Deuerling, and B. Bukau. "The Amino-terminal 118 Amino Acids of Escherichia Coli Trigger Factor Constitute a Domain that is Necessary and Sufficient for Binding to Ribosomes." JBC 272 (1997): 21865-21871. Ullers, et al. "Interplay of Signal Recognition Particle and Trigger Factor at L23 Near the Nascent Chain Exit Site on the Escherichia coli Ribosome." Journal of Cell Biology 161 (2003): 679-684. Li, Z., C. Liu, L. Zhu, G. Jing, and J. Zhou. "The Chaperone Activity of Trigger Factor is Distinct from its Isomerase Activity during Co-expression with Adenylate Kinase in Escherichia Coli." FEBS 506 (2001): 108-112. Scholz, C., G. Stoller, T. Zarnt, G. Fischer, and F. Schmid. "Cooperation of Enzymatic and Chaperone Functions of Trigger Factor in the Catalysis of Protein Folding." EMBO Journal 16 (1997): 54-58. Lyon, William, and Michael, Caparon. "Trigger Factor-Mediated Prolyl Isomerization Influences Maturation of the Streptococcus pyogenes Cysteine Protease." Journal of Bacteriology 185 (2003): 3661-3667. |
| 13 | Functions of prolyl hydroxylases in collagen chain folding and maturation | Prolyl hydroxylase is responsible for the formation of hydroxyproline on newly synthesized chains and is thought to be involved in regulating triple helix formation. Underhydroxylation of prolines is the molecular defect in scurvy, vitamin C deficiency. Myllyharju, J., and K. I. Kivirikko. "Identification of a Novel Proline-rich Peptide Binding Domain in Prolyl-4-hydroxylase." EMBO J 18 (1999): 306-312. Kivirikko, K. I., R. Myllyla, and T. Pihlajaniiemi. "Protein Hydroxylation: Prolyl-4-hydroxylase an Enzyme with Four Cosubstrates and a Multifunctional Subunit." FASEB J 3 (1989): 1609-1617. Walmsely, A. R., M. R. Batten, U. Lad, and N. J. Bulleid. "Intracellular Retention of Procollagen Within the Endoplasmic Reticulum is Mediated by Prolyl4-hydrozylase." J Biol Chem 274 (1999): 14884-14892. |
| 14 | The role of prolyl isomerase in protein folding | What is the role of proline isomerization and proline isomerase in the folding of newly synthesized polypeptide chains within cells, including procollagen? Prolyl isomerase, originally called cyclophilin is the target of the cyclosporin class of immunosuppressive drugs. It turns out to function in many unexpected cellular processes. Harding, M. W., A. Galat, D. E. Uehling, and S. L. Schreiber. "A Receptor for the Immunosuppressant FK506 is a Cis-trans Peptidyl-prolyl Isomerase." Nature 341 (1989): 761-763. Fisher, G., B. Wittman-Liebold, K. Lank, T. Kiefhaber, and F. X. Schmid. "Cyclophlin and Peptidyl-prolyl Cis-trans Isomerase are Probablyidentical Proteins." Nature 337 (1989): 476-478; Steoinman, B., P. Bruckner, and A. Superti-Fuga. "Cyclosporin A Slows Collagen Triple Helix Formation in vivo." (1991). |
| 15 | Prokaryotic proteins involved in disulfide bond formation | Genetic studies in bacteria have identified a family of proteins involved in reduction and oxidation of thiols, and presumed to be involved in the folding of some proteins. |
| 16 | The role of protein disulfide isomerase in the endoplasmic reticuluum | How are disulfide bonds formed in newly synthesized polypeptide chains destined for export from eukaryotic cells? |
| 17 | In Vivo folding and assembly of the influenza hemagglutinin | The intracellular assembly and maturation of this trimeric viral coat protein is one of the better model systems in eukaryotic cells. |
| 18 | The secB chaperonins in proteins destined for export | A number of proteins destined for export (and perhaps folding) outside the cell must be maintained in a non-folded state after synthesis. Some of those are maintained in this state by the secB protein of E.coli, whose mechanism has been studied in considerable detail. |
| 19 | Function of the lens chaperone alpha-crystallin | This is a member of the small heat shock chapeorone family. It is present at high coneentratons in the lens and is thought to protect lens crystallins from radiative or oxidative damage leading to cataract. Horvitz, J. "Alpha-Crystallin can Function as a Molecular Chaperone." Proc Natl Acad Sci USA 89 (1992): 10449-10453. Litt, M., P. Kramer, D. M. LaMorticella, W. Murphey, E. W. Loverien, and R. G. Weleber. "Autosomal Dominant Congenital Cataract Associated with a Missense Mutation in Human Alpha Crystallin Gene CRYAA." Hum Mol Genet 7 (1998): 471-474. Van Montfort, R. L. M., E. Basha, K. L. Friderich, C. Slingsby, and E. Vierling. "Crystal Structure and Assembly of a Eukaryotic Small Heat Shock Protein." Nat Struct Biol 8 (2001): 1025-1030. Tanksale, A., M. Ghatge, and V. Deshpande. "Alpha-Crystallin Binds to the Aggregation-prone Molten-globule of Alkaline Proteases: Implications for Preventing Irreversible Thermal Denaturation." Prot Sci 11 (2002): 1720-1728. |
| 20 | The mechanism of GroE function in protein folding and assembly | How does the chaperone actually function in ensuring productive protein folding? How does the Jack in the Box work, how is ATP hydrolysis coupled to chaperone function? What is the relationship of GroES binding and release to folding within the GroEL lumen? |
| 21 | Chaperonin function in bacterial pilus assembly | Bacteria use extra cellular flagelli and pili for swimming, attaching to other cells and transporting DNA. The folding and assembly of the proteins for these organelles utilize specialized chaperonins some of which function in the bacterial periplasm. These function both in chain folding and in polymerization of the extracellular pilus organelle. Kuehn, M. J., S. Normark, and S. J. Hultgren. "Immunoglobulin-like PapD Chaperone Caps and Uncaps Interactive Surfaces of Nascently Translocated Pilus Subunits." Proc Natl Acad Sci USA 88 (1991): 10586-10590. Slonim, L. N., J. S. Pinkner, C-I, Brändén, and S. J. Hultgren. "Interactive Surface in the PapD Chaperone Cleft is Conserved in Pilus Chaperone Superfamily and Essential in Subunit Recognition and Assembly." EMBO J 11 (1992): 4747-4756. Dodson, K., F. Jacob-Dubuisson, R. Striker, and S. J. Hultgren. "Outer Membrane PapC usher Discriminately Recognizes Periplasmic Chaperone-pilus Subunit Complexes." Proc Natl Acad Sci USA 90 (1993): 3670-3674. Jones, C. H., J. Pinkner, A. Nicholes, L. Slonim, S. Abraham, and S. J. Hultgren. "FimC is a Periplasmic PapD-like Chaperone which Directs Assembly of Type pili in Bacteria." Proc Natl Acad Sci USA 90 (1993): 8397-8401. Kuehn, M. J., D. J. Ogg, J. Kihlberg, L. N. Slonim, K. Flemmer, T. Bergfors, and S. J. Hultgren. "Structural Basis of Pilus Subunit Recognition by the PapD Chaperone." Science 262 (1993): 1234-1241. |
| 22 | Channels for protein import and export | Many newly synthesized proteins have to transit a membrane, for example, for import into mitochondria or for entry to the endoplasmic reticulum. In general, the polypeptide chains have to be maintained in an unfolded state. The proteins forming these channels have recently been identified in a number of organisms. |
| 23 | Function of the DNA K (HSP70) class of chaperonins | These appear to interact with newly synthesized chains at an earlier stage in folding than the GroE class, and function as a complex of DNA K, DNA J, and Grp E. They do not have a lumen, but appear to bind an unfolded peptide in an elongated cleft. Frydman, J., E. Nimmesgern, K. Ohtsuka, and F. U. Hartl. "Folding of Nascent Polypeptide Chains in a High Molecular Mass Assembly with Molecular Chaperones." Nature 370 (1994): 111. Zhu, X., et al. "Structural Analysis of Substrate Binding by the Molecular Chaperone DNAK." Science 272 (1996): 1606. Langer, et al. "Successive Action of DNAK, DNAJ, and Gro EL along the Pathway of Chaperone Assisted Protein Folding." Nature 356 (1992): 683. Szabo, et al. "A Zinc-finger like Domain of the Molecular Chaperone DNAJ is Involved in Binding to Denatured Protein Substrates." EMBO J 15 (1996): 408. |
| Protein misfolding and disease | ||
| 24 | Amyloid deposits in Alzheimers disease | Alzheimers patients have insoluble protein deposits in a number of their tissues. A major class are characterized by a distinctive cross beta rod structure. Jarret, et al. Biochemistry 32 (1993): 4693-4697; Harper, J. D., C. M. Leber, and P. T. Lansbury. "Atomic Force Microscopic Imaging of Seeded Fibril Formation and Fibril Branching by the Alzheimer's Disease Amyloid-beta Protein." Chem Biol 4 (1997): 951-959.
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| 25 | The anti-trypsin defect in familial lung disease | Increased susceptibility to lung damage from smoking and dusts is associated with certain alleles of the anti-elastase that functions in the lung. Recent evidence reveals that their major familial form is due to a defect in the folding of the protein. Ryu, S. E., H. J.Choi, K. S. Kwon, K. N. Lee, and M. H. Yu. "The Native Strains in the Hydrophobic Core and Flexible Reactive Loop of a Serine Protease Inhibitor: Crystal Structure of an Uncleaved Alpha1-antitrypsin at 2.7 Å." Structure 4 (1996): 1181-1192. Kim, S. -J., J. -R. Woo, E. J. Seo, M. -H. Yu, and S. -E. Ryu. "A 2.1 Å Resolution Structure of an Uncleaved Alpha1-antitrypsin Shows Variability of the Reactive Center and Other Loops." J Mol Biol 306 (2001): 109-119. Cabrita, L. D., W. Dai, and S. P. Bottomley. "Different Conformational Changes Within the F-helix Occur During Serpin Folding, Polymerization, and Proteinase Inhibition." Biochemistry 43 (2004): 9834-9. Im, H., M. S. Woo, K. Y. Hwang, and M. H. Yu. "Interactions Causing the Kinetic Trap in Serpin Protein Folding." J Biol Chem 277 (2002): 46347-54. Devlin, G. L., M. K. Chow, G. J. Howlett, and S. P. Bottomley. "Acid Denaturation of Alpha1-antitrypsin: Characterization of a Novel Mechanism of Serpin Polymerization." J Mol Biol 324 (2002): 859-70. Carrell, R. W., and B. Gooptu. "Conformational Changes and Disease- Serpins Prions and Alzheimer's." Curr Opin Struct Biol 8 (1998): 799-809. Carrell, R. W., J. Whisstock, and D. A. Lomas. "Conformational Changes in the Serpins and the Mechanism of Alpha-1 Antichymotrypsin Deficiency." Amer J Respir Crit Care Med 150 (1994): 171-175. |
| 26 | The CFTR defect in cystic fibrosis | Cystic fibrosis is due to a defect in the chloride transporter protein in the respiratory tract. Recent evidence indicates that the most common inherited form is due to a protein folding defect. This is the most developed model of the role of protein folding defects in human disease. |
| 27 | Lens crystallins and cataracts | The proteins of the lens, crystallins, have a variety of unusual properties, at least at high concentrations. The three-dimensional fold of the Gamma crystallin has been solved and the protein can be refolded in vitro. Rare inherited cases of juvenile-onset cataract are due to crystals formed in situ. A variety of indirect evidence suggests that mature-onset cataracts represent the aggregation or polymerization of partially folded forms of these proteins. Heon, E., M. Priston, D. F. Schorderet, G. D. Billingsley, P. O. Girard, N. Lubsen, and F. L. Munier. "The g-Crystallins and Human Cataracts: A Puzzle Clearer." Am J Hum Genet 65 (1999):1261-1267. Pande, A., J. Pande, N. Asherie, A. Lomakin, O. Ogun, J. A. King, and G. B. Benedek. "Crystal Cataracts: Human Genetic Cataract Caused by Protein Crystallization." Proc Natl Acad Sci USA 98 (2001): 6116-6120. Hanson, S. R. A., A. Hasan, D. L. Smith, and J. B. Smith. "The Major in vivo Modifications of the Human Water-insoluble Lens Crystallins are Disulfide Bonds, Deamidation, Methionine Oxidation, and Backbone Cleavage." Exp Eye Res 71 (2000): 195-207. Kosinski-Collins, M., and J. King. "In Vitro Unfolding, Refolding, and Polymerization of Human gD Crystallin, a Protein Involved in Cataract Formation." Protein Science 12 (2003): 480-490. Kosinski-Collins, M., S. Flaugh, and J. King. "Probing Folding and Fluorescence Quenching in Human gD Crystallin Greek Key Domains using Triple Tryptophan Mutant Proteins." Protein Science 13 (2004): 2223-2235. |
| 28 | Parkinson's disease and alpha-synuclein aggregation | Parkinson's disease, due to damage to a very specific region of the brain, is associated with aggregation of a plentiful brain protein alpha-synuclein.
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| 29 | Prion diseases as protein association phenomoma | The evidence is accumulating that prion diseases are due to proteins which change their conformation irreversibly during an association reaction, perhaps by mechanisms related to amyloid accumulation.
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| 30 | Light chain amyloidosis | Cancer patients with a form of leukemia called multiple myeloma often accumulate amyloid deposits composed of the overproduced light chains. Aspects of this aggregation reaction have been elucidated through in vitro experiments. |
| 31 | Superoxide Dismutase defect in ALS (Lou Gehrig's Disease) | Recent evidence indicates that amylotrophic lateral sclerosis is associated with a defect in the function of the widely distributed protein Superoxide Dismutase. The associated amino acid substitution may affect folding or stability rather than metabolic function. Rakhit, R., J. P. Crow, J. R. Lepock, L. H. Kondejewski, N. R. Cashman, and A. Chakrabartty. "Monomeric Cu,Zn-superoxide Dismutase is a Common Misfolding Intermediate in the Oxidation Models of Sporadic and Familial Amyotrophic Lateral Sclerosis." J Biol Chem 279 (2004): 15499-504. Valentine, J. S., and P. J. Hart. "Misfolded CuZnSOD and Amyotrophic Lateral Sclerosis." Proc Natl Acad Sci USA 100, no. 7 (2003): 3617-22. Stathopulos, P. B., J. A. Rumfeldt, G. A. Scholz, R. A. Irani, H. E. Frey, R. A. Hallewell, J. R. Lepock, and E. M. Meiering. "Cu/Zn Superoxide Dismutase Mutants Associated with Amyotrophic Lateral Sclerosis Show Enhanced Formation of Aggregates in vitro." Proc Natl Acad Sci USA 100, no. 12 (2003): 7021-6. |
| 32 | Trans-thyretin and amyloid disease | A rare but well studied class of amyloid diseases are due to deposition of the carrier protein trans-thyretin which is a retinol carrier protein. Features of the in vitro unfolding/ refolding reaction correlate with the conditions that yield pathology. Lashuel, H., Z. Lai, and J. W. Kelly. "Characterization of the Transthyretin Acid Denaturation Pathways by Analytical Ultracentrifugation: Implications for Wild-type, V30M, and L55P Amyloid Fibril Formation." Biochemistry 37 (1998): 17851-17864. Colon, W., and J. W. Kelly. "Partial Denaturation of Transthyretin is Sufficient for Amyloid Fibril Formation in vitro." Biochemistry 31 (1992): 8654-8660. Lai, Z., W. Colon, and J. W. Kelly. "The Acid-mediated Denaturation of Transthyretin Proceeds Through an Intermediate that Partitions into Amyloid." Biochemistry 35 (1996): 6470-6482. Reixach, N., S. Deechongkit, X. Jiang, J. W. Kelly, and J. N. Buxbaum. "Tissue Damage in the Amyloidoses: Transthyretin Monomers and Nonnative Oligomers are the Major Cytotoxic Species in Tissue Culture." Proc Natl Acad Sci USA 101, no. 9 (2004): 2817-22. |
| 33 | Mutations in tumor suppressor proteins | Loss of function of a number of cellular proteins, which control DNA replication and cell division, is associated with tumor formation. Particularly well-studied are p%3 and p21. There is considerable evidence for the p16 ankyrin proteins that some of these mutations may represent protein folding defects. |
| 34 | Protein aggregation in Huntington's disease | The modified protein product associated with CCC expansions in Huntington's disease has recently been identified. The presence of polyglutamine insertions and expansions appears to be a more general source of cellular pathology. An aggregated form of Huntington's is found within the cell nucleus.
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