Thermodynamics of Model Prions and its Implications for the Problem of Prion Protein Folding

Prion disease is caused by the propagation of a particle containing PrP Sc , a misfolded form of the normal cellular prion protein (PrP C ). PrP C can refold to form PrP Sc with loss of a-helical structure and formation of extensive b-sheet structure. Here, we model this prion folding problem with a simple, low-resolution lattice model of protein folding. If model proteins are allowed to re-fold upon dimerization, a minor proportion of them (up to 17 %) encrypts an alternative native state as a homodimer. The structures in this homodimeric native state re-arrange so that they are very different in conformation from the monomeric native state. We find that model proteins that are relatively less stable as monomers are more susceptible to the formation of alternative native states as homodimers. These results suggest that less-stable proteins have a greater need for a well-designed energy landscape for protein folding to overcome an increased chance of encrypting substantially different native conformations stabilized by multimeric interactions. This conceptual framework for aberrant folding should be relevant in Alzheimer’s disease and other disorders associated with protein aggregation. # 1999 Academic Press

[1]  P. Nilsson,et al.  Properties of the scrapie prion protein: quantitative analysis of protease resistance. , 1994, Biochemistry.

[2]  S. Prusiner,et al.  Prion diseases and neurodegeneration. , 1994, Annual review of neuroscience.

[3]  N. Wingreen,et al.  Emergence of Preferred Structures in a Simple Model of Protein Folding , 1996, Science.

[4]  F E Cohen,et al.  A conformational transition at the N terminus of the prion protein features in formation of the scrapie isoform. , 1997, Journal of molecular biology.

[5]  K Wüthrich,et al.  NMR characterization of the full‐length recombinant murine prion protein, mPrP(23–231) , 1997, FEBS letters.

[6]  R. Wickner,et al.  The prion model for [URE3] of yeast: spontaneous generation and requirements for propagation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  E. Shakhnovich,et al.  Theory of kinetic partitioning in protein folding with possible applications to prions , 1998, Proteins.

[8]  Andrew F. Hill,et al.  Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD , 1996, Nature.

[9]  J Moult,et al.  Local interactions dominate folding in a simple protein model. , 1996, Journal of molecular biology.

[10]  P E Wright,et al.  Structure of the recombinant full-length hamster prion protein PrP(29-231): the N terminus is highly flexible. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[11]  F E Cohen,et al.  Solution structure of a 142-residue recombinant prion protein corresponding to the infectious fragment of the scrapie isoform. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[12]  J Q Trojanowski,et al.  Molecular basis of phenotypic variability in sporadc creudeldt‐jakob disease , 1996, Annals of neurology.

[13]  Stephen J. DeArmond,et al.  Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication , 1990, Cell.

[14]  R J Fletterick,et al.  Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Lindquist,et al.  Mad Cows Meet Psi-chotic Yeast: The Expansion of the Prion Hypothesis , 1997, Cell.

[16]  S. Prusiner,et al.  Evidence for the Conformation of the Pathologic Isoform of the Prion Protein Enciphering and Propagating Prion Diversity , 1996, Science.

[17]  P. Lansbury,et al.  Non-genetic propagation of strain-specific properties of scrapie prion protein , 1995, Nature.

[18]  L. Hood,et al.  Structural studies of the scrapie prion protein using mass spectrometry and amino acid sequencing. , 1993, Biochemistry.

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

[20]  S W Liebman,et al.  Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. , 1995, Science.

[21]  R J Fletterick,et al.  Structural clues to prion replication. , 1994, Science.

[22]  K. Dill,et al.  ‘‘Sequence space soup’’ of proteins and copolymers , 1991 .

[23]  K. Dill,et al.  Comparing folding codes for proteins and polymers , 1996, Proteins.

[24]  M. Hurle,et al.  A role for destabilizing amino acid replacements in light-chain amyloidosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Y. Chernoff,et al.  Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. , 1996, Genetics.

[26]  F E Cohen,et al.  The prion folding problem. , 1997, Current opinion in structural biology.

[27]  K. Dill,et al.  The effects of internal constraints on the configurations of chain molecules , 1990 .

[28]  K. Dill,et al.  From Levinthal to pathways to funnels , 1997, Nature Structural Biology.

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

[30]  G J Williams,et al.  The Protein Data Bank: a computer-based archival file for macromolecular structures. , 1977, Journal of molecular biology.

[31]  F. Cohen,et al.  Eight prion strains have PrPSc molecules with different conformations , 1998, Nature Medicine.

[32]  Todd M. Przybycien,et al.  Secondary structure characterization of beta-lactamase inclusion bodies. , 1994, Protein engineering.

[33]  S. Prusiner,et al.  Scrapie prion liposomes and rods exhibit target sizes of 55,000 Da. , 1988, Virology.

[34]  R. Wickner.  A new prion controls fungal cell fusion incompatibility. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  P. Lansbury,et al.  The chemistry of scrapie infection: implications of the 'ice 9' metaphor. , 1995, Chemistry & biology.

[36]  D Thirumalai,et al.  Factors governing the foldability of proteins , 1996, Proteins.

[37]  Eugene I. Shakhnovich,et al.  Enumeration of all compact conformations of copolymers with random sequence of links , 1990 .

[38]  K. Wüthrich,et al.  Prion-inducing domain 2-114 of yeast Sup35 protein transforms in vitro into amyloid-like filaments. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Jernigan,et al.  Residue-residue potentials with a favorable contact pair term and an unfavorable high packing density term, for simulation and threading. , 1996, Journal of molecular biology.

[40]  D Eisenberg,et al.  3D domain swapping: A mechanism for oligomer assembly , 1995, Protein science : a publication of the Protein Society.

[41]  F E Cohen,et al.  Pathologic conformations of prion proteins. , 1998, Annual review of biochemistry.

[42]  Christopher M. Dobson,et al.  Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis , 1997, Nature.

[43]  D. Yee,et al.  Principles of protein folding — A perspective from simple exact models , 1995, Protein science : a publication of the Protein Society.

[44]  D. Thirumalai,et al.  Kinetics of Folding of Proteins and RNA , 1996 .

[45]  J. Kelly,et al.  Comparison of lethal and nonlethal transthyretin variants and their relationship to amyloid disease. , 1995, Biochemistry.

[46]  F. Cohen,et al.  Prion Protein Biology , 1998, Cell.

[47]  K. Dill,et al.  Modeling the effects of mutations on the denatured states of proteins , 1992, Protein science : a publication of the Protein Society.

[48]  F. Cohen,et al.  Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[49]  F. Cohen,et al.  Physical studies of conformational plasticity in a recombinant prion protein. , 1997, Biochemistry.

[50]  C. Sander,et al.  Database of homology‐derived protein structures and the structural meaning of sequence alignment , 1991, Proteins.

[51]  S. Prusiner,et al.  Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. , 1996, Genes & development.