Lesson 7. Unstructured proteins and prions

  1. Intrinsically disordered proteins (and regions) (IDPs)

  2. Ligand binding associated folding

  3. The database DisProt

  4. Prions as infectious agents.

  5. Prions as functional elements of an organism.

  6. Prions are present in all kinds of organisms, including us. Server PrionScan

Nobel Prize in Physiology or Medicine 1997 to Stanley B. Prusiner

"For his discovery of Prions- a new biological principle of infection"

  1. Intrinsically disordered proteins (and regions) (IDPs). Intrinsically disordered proteins (IDPs) lack a stable tertiary structure under physiological conditions. Around the 10% of all proteins are entirely disordered. About 40% of eukaryotic proteins contain at least one messy long segment. The disordered regions present extended, flexible conformations, without a packed nucleus. IDPs and disordered regions are rich in polar residues. Many IDPS present sequences of low complexity with overrepresentation of a few residues.
  2. Ligand binding associated foldingAlgunas IDPs se pliegan al unirse a sus dianas (pequeñas moléculas, sustratos, cofactores, ácidos nucleicos, membranas, otras proteínas). En otros casos, las regiones desordenadas actúan simplemente como conectores flexibles entre dos dominios.
  3. The DisProt database. Structurally characterized IDPs are deposited in DisProt. The main method of structural characterization of IDPS is NMR. The absence of electron density in a segment of a protein can indicate disorder. There are many other biophysical methods que detectan desorden en proteínas aunque no permitan resolver estructuras.
  4. Prions as infectious agents. Los priones son proteínas infecciosas que producen enfermedades neurológicas transmisibles. En el s. XVIII, ganaderos europeos describieron el scrapie (tembladera): una enfermedad de ovejas y cabras cuyos cerebros tenían aspecto de esponja (en vacas se denomina: encefalopatía espongiforme bovina). A principios del siglo XX se describio la enfermedad en humanos (enfermedad de Creutzfeldt-Jakob, Kuru). El termino prión (proteinaceous and infectious) coined it in 1982 by Stanley B. Prusiner (1997 Nobel Prize in Medicine). The causative prion is the PrP proteinc, a sialoglycoprotein of neurons with unknown function, which binds Cu2+. It has two conformations: the non-pathogenic or cellular (PrPc) and the pathogenic or prion (PrPSc). They both have the same sequence but PrPC is rich in alpha and PrP helicesSc in beta sheets and it is resistant to proteases. The disease can appear: -by inherited mutations, -by inoculation or ingestion of PrPSc, -by sporadic conversion of PrPc to PrPSc (90 % of cases). The most striking thing is the transmission: when a prion (PrPsc) enters a healthy organism, converts the normal form into a prion and ends up appearing amyloid fibers. There are other human neurological diseases (Huntington's, Alzheimer's), not related to prions, in which amyloid fibers also develop. These fibers may not cause the diseases and are just symptoms of the diseases. Products are being sought that can cross the blood-brain barrier and prevent the conversion of the normal protein or favor the elimination of the altered one.
  5. Prions as functional elements of an organism. The essential characteristic of prions (transmitting a phenotypic character through a conformational change) is found in other proteins not associated with diseases and whose functions are beginning to be understood. The best known are fungal prions, natural proteins that through conformational change become self-propagating and transmissible, acting as epigenetic elements that transmit information not encoded in DNA.
    • Podospora anserina forms colonies whose cells fuse and share the cytoplasmic content. The HET-s prion extends between the cells of the colony. When cells from another incompatible colony attempt to fuse, the prion kills them, ensuring that only cells from related colonies benefit from sharing matter.
    • The prion [GAR+] from yeast confers resistance to glucose repression from the use of alternative carbon sources.
    • Yeast Mod5 prion regulates sterol biosynthesis to achieve fungicide resistance. The presence of fungicides induces the conversion of Mod5 into the prion form.
  1. Prions are present in all kinds of organisms, including us.  Los priones conocidos tienen regiones con composiciones de aminoácidos peculiares (i.e. ricas en Q/N). Basándonos en este hecho hemos desarrollado una metodología de predicción de priones en genomas completos que se puede consultar en el servidor PrionScan. Hemos encontrado priones en virus, arqueas, bacterias, plantas, hongos y animales. En animales los priones tiendes a ser proteinas nucleares de union a DNA y RNA. El 0.5 % del genoma humano codifica proteínas potencialmente prionicas.