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Anfinsen's dogma
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<h2 id="challenges-to-anfinsens-dogma">Challenges to Anfinsen's dogma</h2> <p><a href="/facts/Protein_folding/rf3nR2Y1">Protein folding</a> in a cell is a highly complex process that involves transport of the newly synthesized proteins to appropriate cellular compartments through <a href="/facts/Protein_targeting/R3B37xMM">targeting</a>, <a href="/facts/Proteopathy/woWrXMXM">permanent misfolding</a>, <a href="/facts/Intrinsically_disordered_proteins/KrnRkv7K">temporarily unfolded states</a>, <a href="/facts/Post-translational_modifications/KMUayTIc">post-translational modifications</a>, quality control, and formation of <a href="/facts/Protein_complexes/GW11Ee34">protein complexes</a> facilitated by <a href="/facts/Protein_chaperones/2SAjcVnW">chaperones</a>. </p><p>Some proteins need the assistance of <a href="/facts/Chaperone_(protein)/2SAjcVnW">chaperone proteins</a> to fold properly. It has been suggested that this disproves Anfinsen's dogma. However, the chaperones do not appear to affect the final state of the protein; they seem to work primarily by preventing <a href="/facts/Protein_aggregation/94Ad1VqG">aggregation</a> of several protein molecules prior to the final folded state of the protein. However, at least some chaperones are required for the proper folding of their subject proteins.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p><p>Many proteins can also undergo aggregation and <a href="/facts/Proteopathy/woWrXMXM">misfolding</a>. For example, <a href="/facts/Prion/UJfG9EfS">prions</a> are stable conformations of proteins which differ from the native folding state. In <a href="/facts/Bovine_spongiform_encephalopathy/UKYCrfRh">bovine spongiform encephalopathy</a>, native proteins re-fold into a different stable conformation, which causes fatal <a href="/facts/Amyloid/IjBcvNvV">amyloid</a> buildup. Other amyloid diseases, including <a href="/facts/Alzheimer%2527s_disease/w7Ad6tdg">Alzheimer's disease</a> and <a href="/facts/Parkinson%2527s_disease/xpekKj6x">Parkinson's disease</a>, are also exceptions to Anfinsen's dogma.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> </p><p>Some proteins have <a href="/facts/Protein_dynamics/YGd6hP9U">multiple native structures</a>, and change their fold based on some external factors. For example, the KaiB protein complex <a href="/facts/KaiB/4z4pjKl6">switches fold throughout the day</a>, acting as a clock for cyanobacteria. It has been estimated that around 0.5–4% of <a href="/facts/Protein_Data_Bank/oUhq4ABD">Protein Data Bank</a> (PDB) proteins switch folds.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> The switching between alternative structures is driven by interactions of the protein with small ligands or other proteins, by chemical modifications (such as <a href="/facts/Protein_phosphorylation/4alcRDkM">phosphorylation</a>) or by changed environmental conditions, such as temperature, pH or <a href="/facts/Membrane_potential/DpNG14c7">membrane potential</a>. Each alternative structure may either correspond to the global minimum of <a href="/facts/Gibbs_free_energy/bvenDuzh">free energy</a> of the protein at the given conditions or be <a href="/facts/Chemical_kinetics/D8vyX4aE">kinetically</a> trapped in a higher <a href="/facts/Local_minimum/ADlgnyzV">local minimum</a> of free energy.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="further-reading">Further reading</h2> <ul><li>Sela M, White FH Jr, Anfinsen CB (1957). "Reductive cleavage of disulfide bridges in ribonuclease". <i>Science</i>. 125 (3250): 691–692. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1957Sci...125..691S">1957Sci...125..691S</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1126%2Fscience.125.3250.691">10.1126/science.125.3250.691</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/13421663">13421663</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:36895461">36895461</a>.</li> <li>Anfinsen CB, <a href="/facts/Edgar_Haber/4bXIGkRg">Haber E</a> (1961). <a href="https://doi.org/10.1016%2FS0021-9258%2818%2964177-8">"Studies on the reduction and re-formation of protein disulfide bonds"</a>. <i>J. Biol. Chem</i>. 236 (5): 1361–1363. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2FS0021-9258%2818%2964177-8">10.1016/S0021-9258(18)64177-8</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/13683523">13683523</a>.</li> <li>Moore S, Stein WH (1973). "Chemical structures of pancreatic ribonuclease and deoxyribonuclease". <i>Science</i>. 180 (4085): 458–464. <a href="/facts/Bibcode_(identifier)/9HtdQSGB">Bibcode</a>:<a href="https://ui.adsabs.harvard.edu/abs/1973Sci...180..458M">1973Sci...180..458M</a>. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1126%2Fscience.180.4085.458">10.1126/science.180.4085.458</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/4573392">4573392</a>.</li> <li><a href="http://profiles.nlm.nih.gov/ps/browse/ResourceResult/TYPE/Articles/CID/KK/sort/chron">Profiles in Science: The Christian B. Anfinsen Papers-Articles</a></li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Anfinsen CB (1973). "Principles that govern the folding of protein chains". Science. 181 (4096): 223–230. Bibcode:1973Sci...181..223A. doi:10.1126/science.181.4096.223. PMID 4124164. <a href="/wiki/Bibcode_(identifier)" target="_blank">/wiki/Bibcode_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>"Press Release: The 1972 Nobel Prize in Chemistry". Nobelprize.org (Press release). <a href="https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1972/press.html" target="_blank">https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1972/press.html</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>White FH (1961). "Regeneration of native secondary and tertiary structures by air oxidation of reduced ribonuclease". J. Biol. Chem. 236 (5): 1353–1360. doi:10.1016/S0021-9258(18)64176-6. PMID 13784818. <a href="https://doi.org/10.1016%2FS0021-9258%2818%2964176-6" target="_blank">https://doi.org/10.1016%2FS0021-9258%2818%2964176-6</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Anfinsen CB, Haber E, Sela M, White FH Jr (1961). "The kinetics of formation of native ribonuclease during oxidation of the reduced polypeptide chain". PNAS. 47 (9): 1309–1314. Bibcode:1961PNAS...47.1309A. doi:10.1073/pnas.47.9.1309. PMC 223141. PMID 13683522. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC223141" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC223141</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Eisenberg, David S. (June 2018). "How Hard It Is Seeing What Is in Front of Your Eyes". Cell. 174 (1): 8–11. doi:10.1016/j.cell.2018.06.027. PMID 29958112. <a href="https://linkinghub.elsevier.com/retrieve/pii/S0092867418307955" target="_blank">https://linkinghub.elsevier.com/retrieve/pii/S0092867418307955</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Kris Pauwels and other (2007). "Chaperoning Anfinsen:The Steric Foldases" (PDF). Molecular Microbiology. 64 (4): 917–922. doi:10.1111/j.1365-2958.2007.05718.x. PMID 17501917. S2CID 6435829. Archived from the original (PDF) on 2012-05-23. <a href="https://web.archive.org/web/20120523130904/http://ultr23.vub.ac.be/ultr/pub/pdfs/290.pdf" target="_blank">https://web.archive.org/web/20120523130904/http://ultr23.vub.ac.be/ultr/pub/pdfs/290.pdf</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>"Protein Folding and Misfolding". Yale University Rhoades Lab. Archived from the original on 2012-07-19. Retrieved 2012-08-24. <a href="https://web.archive.org/web/20120719110222/http://www.yale.edu/rhoadeslab/research.html" target="_blank">https://web.archive.org/web/20120719110222/http://www.yale.edu/rhoadeslab/research.html</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Porter, Lauren L.; Looger, Loren L. (5 June 2018). "Extant fold-switching proteins are widespread". Proceedings of the National Academy of Sciences. 115 (23): 5968–5973. Bibcode:2018PNAS..115.5968P. doi:10.1073/pnas.1800168115. PMC 6003340. PMID 29784778. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003340" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003340</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Varela, Angela E.; England, Kevin A.; Cavagnero, Silvia (2019). "Kinetic trapping in protein folding". Protein Engineering Design & Selection. 32 (2): 103–108. doi:10.1093/protein/gzz018. PMID 31390019. <a href="https://pubmed.ncbi.nlm.nih.gov/31390019/" target="_blank">https://pubmed.ncbi.nlm.nih.gov/31390019/</a> <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> </ol>