User:Eliška Koutná/Sandbox 3
From Proteopedia
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= '''Prions''' = | = '''Prions''' = | ||
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> | <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> | ||
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== '''General intro''' == | == '''General intro''' == | ||
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The PrPSc differs from PrPC solely in conformation and is its isoform. The mature PrPC consists of approx. 208 amino acids, arranged as a disordered N-terminus and a globular C-terminal domain consisting of three α-helices and a short, antiparallel β-pleated sheet <ref>PMID 10618385</ref><ref>DOI 10.1038/382180a0</ref>. There is a GPI membrane anchor at the C-terminus that tethers the protein to cell membranes and proteins that are secreted and lacking the anchor component has been proven to be unaffected by the infectious isoform <ref>DOI 10.1126/science.1110837</ref>. In contrast to the natural form of prion protein with only about 3 % of β-sheet secondary structure, the PrPSc form has about 47 % of the secondary structure in β-sheets <ref name="pan">PMID 7902575</ref> that create a core of four-rung β-solenoid fold <ref>DOI 10.3390/pathogens7010020</ref>. Accordingly, they also differ in their properties. PrPC is soluble, has a life-span between 2 and 4 hours, and is sensitive to proteolytic cleavage – when exposed to proteases, the protein is degraded completely <ref name="pan" />. The two most important cleavage events are the α cleavage which removes the unstructured N-terminal tail and leaves the globular domain attached to the cell membrane, and the cleavage on the C-terminal end (termed PrPC shedding) which releases PrPC into the extracellular space <ref name="sigurdson">DOI 10.3390/pathogens7010020</ref>. Under the same conditions, PrPSc is hydrolysed by proteases only partially by forming resistant core fragment PrP 27-30 <ref name="pan" />. In addition, it is insoluble in detergents and has a very long half-life, therefore accumulates in tissues easily. It has a tendency to form aggregates and fibrillar structures and is generally susceptible to oligomerization, whereas the PrPC form mainly exist as a monomer <ref name="cohen&prusiner">DOI 10.1146/annurev.biochem.67.1.793</ref>. Monomeric PrPSc has never been isolated. | The PrPSc differs from PrPC solely in conformation and is its isoform. The mature PrPC consists of approx. 208 amino acids, arranged as a disordered N-terminus and a globular C-terminal domain consisting of three α-helices and a short, antiparallel β-pleated sheet <ref>PMID 10618385</ref><ref>DOI 10.1038/382180a0</ref>. There is a GPI membrane anchor at the C-terminus that tethers the protein to cell membranes and proteins that are secreted and lacking the anchor component has been proven to be unaffected by the infectious isoform <ref>DOI 10.1126/science.1110837</ref>. In contrast to the natural form of prion protein with only about 3 % of β-sheet secondary structure, the PrPSc form has about 47 % of the secondary structure in β-sheets <ref name="pan">PMID 7902575</ref> that create a core of four-rung β-solenoid fold <ref>DOI 10.3390/pathogens7010020</ref>. Accordingly, they also differ in their properties. PrPC is soluble, has a life-span between 2 and 4 hours, and is sensitive to proteolytic cleavage – when exposed to proteases, the protein is degraded completely <ref name="pan" />. The two most important cleavage events are the α cleavage which removes the unstructured N-terminal tail and leaves the globular domain attached to the cell membrane, and the cleavage on the C-terminal end (termed PrPC shedding) which releases PrPC into the extracellular space <ref name="sigurdson">DOI 10.3390/pathogens7010020</ref>. Under the same conditions, PrPSc is hydrolysed by proteases only partially by forming resistant core fragment PrP 27-30 <ref name="pan" />. In addition, it is insoluble in detergents and has a very long half-life, therefore accumulates in tissues easily. It has a tendency to form aggregates and fibrillar structures and is generally susceptible to oligomerization, whereas the PrPC form mainly exist as a monomer <ref name="cohen&prusiner">DOI 10.1146/annurev.biochem.67.1.793</ref>. Monomeric PrPSc has never been isolated. | ||
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| + | == '''Misfolding''' == | ||
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| + | The fundamental event in propagation of the infectious form lies in the PrPSc template-directed misfolding of the natural form into the pathogenic, β-sheet-rich version of itself <ref name="pan" />. This process is now widely accepted as a current prion theory, and the most striking fact is that this action lacks any nucleic acid template <ref name="sigurdson" />. However, the replication cycle of PrPSc does need the PRNP gene to direct PrPC synthesis. Also, the interaction between the pathogenic and physiological form must be quite specific to propagate the conversion. The replication process itself can be explained by stochastic fluctuations in the PrPC structure, that would create the intermediate form, PrP*. This partially unfolded monomer can then switch back to the natural conformation, adopt a PrPSc one, or be degraded. Normally, there is an equilibrium between the PrPC and PrP* states which favors the physiological one. Depending on the specific cause of the disease, the PrP* state can adopt a PrPSc conformation either upon contant with a dimer of this infectious form by forming a heteromultimer which is further converted into a homomultimer of PrPSc, or through encounter with another PrP* molecule. This PrP*/PrP* dimer can then form an infectious dimer and initiate the replication cycle <ref name="cohen">DOI 10.1126/science.7909169</ref> <ref name="cohen&prusiner" />. It has been found that certain host-specific RNAs can assist with the conversion into the pathogenic form <ref>DOI 10.1038/nature01979</ref>. | ||
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== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 15:02, 15 May 2019
Prions
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