Editing Proteasome (section)

==== Conformational changes of 19S ====
These initial structures showed that the 19S RP adopted a number of states (termed s1, s2, s3, and s4 in yeast) which provided a model for how substrates were recruited and subsequently degraded by the proteasome.<ref name="Unverdorben">{{cite journal |vauthors=Unverdorben P, Beck F, Śledź P, Schweitzer A, Pfeifer G, Plitzko JM, Baumeister W, Förster F |date=April 2014 |title=Deep classification of a large cryo-EM dataset defines the conformational landscape of the 26S proteasome |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=111 |issue=15 |pages=5544–9 |bibcode=2014PNAS..111.5544U |doi=10.1073/pnas.1403409111 |pmc=3992697 |pmid=24706844 |doi-access=free}}</ref><ref name="Matyskiela">{{cite journal |vauthors=Matyskiela ME, Lander GC, Martin A |date=July 2013 |title=Conformational switching of the 26S proteasome enables substrate degradation |journal=Nature Structural & Molecular Biology |volume=20 |issue=7 |pages=781–788 |doi=10.1038/nsmb.2616 |pmc=3712289 |pmid=23770819}}</ref>  A hallmark of the AAA-ATPase configuration in this predominant low-energy state is a staircase- or lockwasher-like arrangement of the AAA-domains.<ref name="Beck" /><ref name="Lander" />   These states could be manipulated upon the addition of ATPgS,<ref name="Sledz" /> substrate, or by the non-essential DUB Ubp6.  The s1 state was proposed to be the resting state of the proteasome, allowing for a protein substrate to engage the AAA motor.  Upon binding a substrate, the proteasome would shift to a processing state, in which a central channel from the top of the AAA motor into the 20S proteolytic chamber would form allowing a direct passage of a substrate from the 19S RP into the proteolytic site.   Subsequent studies with the human proteasome have shown many more sub-states, and provide a model for ATP dependent translocation of a substrate.<ref name="Zhuy">{{cite journal |vauthors=Zhu Y, Wang WL, Yu D, Ouyang Q, Lu Y, Mao Y |date=April 2018 |title=Structural mechanism for nucleotide-driven remodeling of the AAA-ATPase unfoldase in the activated human 26S proteasome |journal=Nature Communications |volume=9 |issue=1 |page=1360 |bibcode=2018NatCo...9.1360Z |doi=10.1038/s41467-018-03785-w |pmc=5893597 |pmid=29636472}}</ref><ref name="Chen" /><ref name="Dong" />

In 2018, the first structure of a processing proteasome bound to a substrate was solved using cryo-EM, confirming biochemistry that showed that de-ubiquitination by Rpn11 was performed in a translocation dependent manner <ref name=":0">{{cite journal |last1=Worden |first1=Evan J. |last2=Dong |first2=Ken C. |last3=Martin |first3=Andreas |title=An AAA Motor-Driven Mechanical Switch in Rpn11 Controls Deubiquitination at the 26S Proteasome |journal=Molecular Cell |date=September 2017 |volume=67 |issue=5 |pages=799–811.e8 |doi=10.1016/j.molcel.2017.07.023|pmid=28844860 }}</ref> and revealing key steps in translocation.<ref name="Substrate-engaged 26 S proteasome s"/>  Subsequently, a major effort has elucidated the detailed structures of deubiquitylation, initiation of translocation and processive unfolding of substrates by determining seven atomic structures of substrate-engaged 26S proteasome simultaneously.<ref name="Dong" />

[[File:3 conformational states of 26S proteasome.jpg|thumb|300px|Three distinct conformational states of the 26S proteasome.<ref name=Unverdorben/> The conformations are hypothesized to be responsible for recruitment of the substrate, its irreversible commitment, and finally processing and translocation into the core particle, where degradation occurs.]]