Protein misfolding and related disease

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  • 7/28/2019 Protein misfolding and related disease.


  • 7/28/2019 Protein misfolding and related disease.


    A Protein is a polymer of amino acids which contains a constant

    backbone of repeating units with a variable side chain attached toeach unit of backbone. Proteins all have the same backbone, theside chains are what distinguish proteins and give their individual

    characteristics.Proteins under ideal conditions such as suitable solvent andtemperature will adopt a stable structure called the native state.Proteins exist in a primary, secondary, tertiary and quaternarystructure.

  • 7/28/2019 Protein misfolding and related disease.






  • 7/28/2019 Protein misfolding and related disease.


    How and whether a protein folds in vivo areinfluenced primarily by its amino acid sequenceand the cellular environment surrounding thepolypeptide chain1. Protein folding in the cell

    occurs either in the cytoplasm or within thesecretory ATP-dependent chaperones in thecytoplasm and the lumen of the endoplasmicreticulum (ER) collaborate to give a polypeptidechain several opportunities to fold. If folding isunsuccessful, the polypeptide is directed to theproteasomea large multisubunit proteasefordegradation. Ensuring accuracy in protein foldingis crucial for maintaining proper cellular function.

  • 7/28/2019 Protein misfolding and related disease.


    Proteolytic cleavage breaks down proteins



    Degradation of protein serves a number of functions


  • 7/28/2019 Protein misfolding and related disease.


    conjugation of multiple ubiquitin moieties to thesubstrate and degradation of the tagged protein by the

    downstream 26S proteasome complex

  • 7/28/2019 Protein misfolding and related disease.


  • 7/28/2019 Protein misfolding and related disease.


    The ubiquitin proteolytic pathway. 1: Activation of ubiquitin bythe ubiquitin-activating enzyme E1, a ubiquitin-carrier protein, E2(ubiquitin-conjugating enzyme, UBC), and ATP. The product ofthis reaction is a high-energy E2ubiquitin thiol esterintermediate.

    2: Binding of the protein substrate, via a defined recognitionmotif, to a specific ubiquitin-protein ligase, E3.

    3: Multiple (n) cycles of conjugation of ubiquitin to the targetsubstrate and synthesis of a polyubiquitin chain. E2 transfers thefirst activated ubiquitin moiety directly to the E3-bound substrate,and in following cycles, to previously conjugated ubiquitin

    moiety. Direct transfer of activated ubiquitin from E2 to the E3-bound substrate occurs in substrates targeted by RING finger E3s.

    3: As in3, but the activated ubiquitin moiety is transferred fromE2 to a high-energy thiol intermediate on E3, before itsconjugation to the E3-bound substrate or to the previouslyconjugated ubiquitin moiety. This reaction is catalyzed by HECTdomain E3s.

    4: Degradation of the ubiquitin-tagged substrate by the 26Sproteasome complex with release of short peptides.

    5: Ubiquitin is recycled via the activity of deubiquitinatingenzymes (DUBs).

  • 7/28/2019 Protein misfolding and related disease.


  • 7/28/2019 Protein misfolding and related disease.


    Complete, rapid, and sustained termination of

    the process

    Ubiquitination and proteolysis of activators evenmay stimulate transcriptional activity

    UPP selectively eliminates abnormally folded or

    damaged proteins


  • 7/28/2019 Protein misfolding and related disease.


    The conversion of a protein into astructure that differs from its native state.

    The improper foldings are generallyeliminated or degraded by ubiquintin-proteasome pathway to ensure high fidelityof protein expression but sometimesproteins escape this process leading toprotein aggregation like

    Loop sheet polymer

    Amyloid fibrils

  • 7/28/2019 Protein misfolding and related disease.


    Graph representing folding and misfolding states.

  • 7/28/2019 Protein misfolding and related disease.


    Protein aggregates having a cross- structure andother characteristics, e.g., specific dye-binding.

    These misfolded structures alter their properconfiguration such that they erroneously interactwith one another or other cell components forminginsoluble fibrils. They have been associated with thepathology of more than 20 serious human diseases

    in that, abnormal accumulation of amyloid fibrils inorgans may lead to amyloidosis, and may play arole in various neurodegenerative disorders.
  • 7/28/2019 Protein misfolding and related disease.



  • 7/28/2019 Protein misfolding and related disease.


    The fibrils can be imaged in vitro using transmission electronmicroscopy (TEM) or atomic force microscopy (AFM). Theseexperiments reveal that the fibrils usually consist of a number(typically 26) of protofilaments, each about 25 nm in diameter.These protofilaments twist together to form ropelike fibrils that aretypically 713 nm wide or associate laterally to form long ribbonsthat are 25 nm thick and up to 30 nm wide. X-ray fiber diffraction

    data have shown that in each individual protofilament theprotein or peptide molecules are arranged so that thepolypeptide chain forms -strands that run perpendicular to thelong axis of the fibril.

  • 7/28/2019 Protein misfolding and related disease.


    The largest group of misfolding diseases, however, is

    associated with the conversion of specific peptides

    or proteins from their soluble functional states

    ultimately into highly organized fibrillar aggregates.These structures are generally described as

    amyloid fibrils or plaques when they accumulate

    extracellularly, whereas the term intracellular

    inclusions has been suggested as moreappropriate when fibrils morphologically and

    structurally related to extracellular amyloid form

    inside the cell.

  • 7/28/2019 Protein misfolding and related disease.


  • 7/28/2019 Protein misfolding and related disease.


    Neurodegenerative disordermost common cause of dementia in elderly

    Clinically, apparent as insidious

    impairment of higher intellectual function,

    with alteration in mood and behavior.

    Later, progressive disorientation, memory loss

    and aphasia, indicate severe cortical


    Later, patient becomes disabled, mute and


  • 7/28/2019 Protein misfolding and related disease.



    Forgetfulness; other memory disturbances

    Language deficits Loss of learned motor skills

    Loss of mathematical skills


    Patient become mute; unable to walk

  • 7/28/2019 Protein misfolding and related disease.


    Individuals with Downs syndrome contain an extra copy ofchromosome 21, (3 in total), and if they survive until middle age, there isalmost a definite probability they will develop AD . This chromosomecontain a gene linked to early-onset AD.

    Chromosome 14 was also found to have a gene (S182) responsible forearly-onset AD, as well as chromosome 1, which contains a gene (STM2)

    responsible for early-onset AD. Other chromosomes are being studied foridentification of AD causing genes.

    Amyloid deposits, (A), in the brain of an individual with AD havepeptide deposits of approximately 40-residues long. Amyloid depositsare the product of their precursor, Amyloid precursor protein (APP),resulting from the action of proteases - and -secretase.

    Aare produced with variable lengths of 40 and 42 residues long, A40

    and A42. The predominant Aproduced in a normal individual is A40.Mutations in the APP gene on chromosome 21 either increases theamyloid levels or just A42 alone.

    The initial deposits of A42 are able to promote the further deposition ofboth A42 and A40, all these amyloid deposits cause the widespreadatrophy.

  • 7/28/2019 Protein misfolding and related disease.


    AD, the most prevalent dementia affecting almost 2% of thepopulation in the western world, The risk of developing ADdramatically increases in people over 70 years.

    The most reliable diagnosis of AD is possible, unfortunately, whenthe individual has deceased, by conducting a post-mortem to

    identify amyloid deposits and neurofibrillary tangles and plaquesin the brain .

    From post-mortem examinations of brains from AD patients,abnormalities can be seen such as wasting away of primarilyfrontal and temporal gyri (up to 20%) and ventricleenlargements. Although, this may be due to ageing.

    The amyloid deposits cause the widespread atrophy (wastingaway) of the cerebral cortex, and also other areas, such as thehippocampus. Tangles and plaques are formed from discardedparts of neurons that have died or shrunk. Tangles are structuresformed from degenerating neuronal cell bodies and plaquesare structures formed from degenerating axons and dendrites

  • 7/28/2019 Protein misfolding and related disease.


    Parkinson disease is a braindisorder. It occurs when certainnerve cells (neuron