Mechanism of proteasome gate modulation by assembly chaperones Pba1 and Pba2

Abstract

The active sites of the proteasome are housed within its central core particle (CP), a barrel-shaped chamber of four stacked heptameric rings, and access of substrates to the CP interior is mediated by gates at either axial end. These gates are constitutively closed and may be opened by the regulatory particle (RP), which binds the CP and facilitates substrate degradation. We recently showed that the heterodimeric CP assembly chaperones Pba1/2 also mediate gate opening through an unexpected structural arrangement that facilitates the insertion of the N terminus of Pba1 into the CP interior; however, the full mechanism of Pba1/2-mediated gate opening is unclear. Here, we report a detailed analysis of CP gate modulation by Pba1/2. The clustering of key residues at the interface between neighboring α-subunits is a critical feature of RP-mediated gate opening, and we find that Pba1/2 recapitulate this strategy. Unlike RP, which inserts at six α-subunit interfaces, Pba1/2 insert at only two α-subunit interfaces. Nevertheless, Pba1/2 are able to regulate six of the seven interfacial clusters, largely through direct interactions. The N terminus of Pba1 also physically interacts with the center of the gate, disrupting the intersubunit contacts that maintain the closed state. This novel mechanism of gate modulation appears to be unique to Pba1/2 and therefore likely occurs only during proteasome assembly. Our data suggest that release of Pba1/2 at the conclusion of assembly is what allows the nascent CP to assume its mature gate conformation, which is primarily closed, until activated by RP. The active sites of the proteasome are housed within its central core particle (CP), a barrel-shaped chamber of four stacked heptameric rings, and access of substrates to the CP interior is mediated by gates at either axial end. These gates are constitutively closed and may be opened by the regulatory particle (RP), which binds the CP and facilitates substrate degradation. We recently showed that the heterodimeric CP assembly chaperones Pba1/2 also mediate gate opening through an unexpected structural arrangement that facilitates the insertion of the N terminus of Pba1 into the CP interior; however, the full mechanism of Pba1/2-mediated gate opening is unclear. Here, we report a detailed analysis of CP gate modulation by Pba1/2. The clustering of key residues at the interface between neighboring α-subunits is a critical feature of RP-mediated gate opening, and we find that Pba1/2 recapitulate this strategy. Unlike RP, which inserts at six α-subunit interfaces, Pba1/2 insert at only two α-subunit interfaces. Nevertheless, Pba1/2 are able to regulate six of the seven interfacial clusters, largely through direct interactions. The N terminus of Pba1 also physically interacts with the center of the gate, disrupting the intersubunit contacts that maintain the closed state. This novel mechanism of gate modulation appears to be unique to Pba1/2 and therefore likely occurs only during proteasome assembly. Our data suggest that release of Pba1/2 at the conclusion of assembly is what allows the nascent CP to assume its mature gate conformation, which is primarily closed, until activated by RP. A key feature of protein degradation by the proteasome and related proteases is the sequestration of their proteolytic active sites within an enclosed chamber. In the case of the eukaryotic proteasome, this chamber is the barrel-shaped 20S core particle (CP), which consists of four stacked heptameric rings. The inner β-rings harbor the three distinct proteolytic active sites. Access of substrates to the CP interior is mediated by the outer α-rings, which contain a gate at either axial end. That gate, however, exists primarily in a closed state and requires an activating mechanism of gate opening to facilitate degradation. The primary CP activator is the 19S regulatory particle (RP), an ∼900 kDa multisubunit complex, which binds to the outer surface of the α-rings to create the full proteasome holoenzyme. In addition to recognizing ubiquitinated substrates, deubiquitinating them, and unfolding them, the RP also opens the CP gate and threads the substrate into the CP interior for proteolysis (1Bard J.A.M. Goodall E.A. Greene E.R. Jonsson E. Dong K.C. Martin A. Structure and function of the 26S proteasome.Annu. Rev. Biochem. 2018; 87: 697-724Crossref PubMed Scopus (295) Google Scholar). The RP can be further divided into lid and base subcomplexes (2Glickmann M.H. Rubin D.M. Coux O. Wefes I. Pfeifer G. Cjeka Z. Baumeister W. Fried V.A. Finley D. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3.Cell. 1998; 94: 615-623Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar). The base contains a heterohexameric ring of AAA-type ATPases known as Rpt1–6, which directly bind to the CP surface. Three of these subunits possess a C-terminal HbYX (hydrophobic-tyrosine-any amino acid) motif (3Smith D.M. Chang S.C. Park S. Finley D. Cheng Y. Goldberg A.L. Docking of the proteasomal ATPases’ carboxyl termini in the 20S proteasome’s α ring opens the gate for substrate entry.Mol. Cell. 2007; 27: 731-744Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar, 4Wehmer M. Rudack T. Beck F. Aufderheide A. Pfeifer G. Plitzko J.M. Förster F. Schulten K. Baumeister W. Sakata E. Structural insights into the functional cycle of the ATPase module of the 26S proteasome.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 1305-1310Crossref PubMed Scopus (97) Google Scholar) which inserts into pockets between neighboring α-subunits with a key-in-lock mechanism. The insertion of both the HbYX-containing and non-HbYX-containing subunits (especially Rpt1 and Rpt6) aligns the RP–CP interface and leads to opening of the CP gate (5Park S. Li X. Kim H.M. Singh C.R. Tian G. Hoyt M.A. Lovell S. Battaile K.P. Zolkiewski M. Coffino P. Roelofs J. Cheng Y. Finley D. Reconfiguration of the proteasome during chaperone-mediated assembly.Nature. 2013; 497: 512-516Crossref PubMed Scopus (58) Google Scholar, 6Eisele M.R. Reed R.G. Rudack T. Schweitzer A. Beck F. Nagy I. Pfeifer G. Plitzko J.M. Baumeister W. Tomko R.J. Sakata E. Expanded coverage of the 26S proteasome conformational landscape reveals mechanisms of peptidase gating.Cell Rep. 2018; 24: 1301-1315.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). A second HbYX-containing CP modulator, the ∼250 kDa monomeric protein Blm10 (PA200 in mammals), also binds to the axial surface of the CP and modulates the gate (7Sadre-Bazzaz K. Whitby F.G. Robinson H. Formosa T. Hill C.P. Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate opening.Mol. Cell. 2010; 37: 728-735Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). However, the gate in Blm10–CP complexes is largely disordered with at most a partially open conformation, and the precise function of Blm10 remains uncertain. A third CP activator, PA28, is absent from yeast. Interestingly, and unlike RP and Blm10, PA28 does not possess the HbYX motif (8Förster A. Whitby F.G. Hill C.P. The pore of activated 20S proteasomes has an ordered 7-fold symmetric conformation.EMBO J. 2003; 22: 4356-4364Crossref PubMed Scopus (92) Google Scholar). HbYX motifs are also found in the proteins Pba1 and Pba2, which are CP assembly chaperones that “cap” the CP in a manner analogous to the RP and Blm10 (9Hirano Y. Hendil K.B. Yashiroda H. Iemura S.I. Nagane R. Hioki Y. Natsume T. Tanaka K. Murata S. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes.Nature. 2005; 437: 1381-1385Crossref PubMed Scopus (188) Google Scholar, 10Li X. Kusmierczyk A.R. Wong P. Emili A. Hochstrasser M. β-Subunit appendages promote 20S proteasome assembly by overcoming an Ump1-dependent checkpoint.EMBO J. 2007; 26: 2339-2349Crossref PubMed Scopus (114) Google Scholar). Pba1/2 associate early during the assembly process and are released only upon completion of assembly. Binding of Pba1/2 or RP to the CP appears to be mutually exclusive, and one function of Pba1/2 is thought to be prevention of premature activation of the CP by RP; Pba1/2 are also thought to prevent ring (9Hirano Y. Hendil K.B. Yashiroda H. Iemura S.I. Nagane R. Hioki Y. Natsume T. Tanaka K. Murata S. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes.Nature. 2005; 437: 1381-1385Crossref PubMed Scopus (188) Google Scholar, W. K. S. X. A. J. Yashiroda H. Murata S. proteasome assembly the core assembly in the 2018; PubMed Scopus Google Scholar, M.A. A. Roelofs J. of the proteasome core particle an that regulatory particle PubMed Scopus Google Scholar). The HbYX motifs of Pba1/2 also insert into pockets and to with residues that E. K. Robinson H. D.M. Formosa T. Hill C.P. Structure of a proteasome complex for proteasome and Full Text Full Text PDF PubMed Scopus Google Scholar). However, has for an open gate during CP assembly in of Pba1/2 with mature CP to the CP in E. K. Robinson H. D.M. Formosa T. Hill C.P. Structure of a proteasome complex for proteasome and Full Text Full Text PDF PubMed Scopus Google Scholar). of CP assembly a unexpected structural arrangement the N terminus of Pba1 is through an open gate into the CP interior contacts of the assembly H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google These that to the RP, are of an open gate however, the CP pore is by the N terminus of Pba1/2 to CP in The process of RP-mediated gate opening is two of gate opening The CP gate is by the N termini of the α-subunits M. M. A. Rubin D.M. R. M.H. Finley D. A into the proteasome core PubMed Scopus Google Scholar). In the closed is a critical between the N termini of that for of the at the center of the The residues in in and and in M.R. Reed R.G. Rudack T. Schweitzer A. Beck F. Nagy I. Pfeifer G. Plitzko J.M. Baumeister W. Tomko R.J. Sakata E. Expanded coverage of the 26S proteasome conformational landscape reveals mechanisms of peptidase gating.Cell Rep. 2018; 24: 1301-1315.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, M. M. A. Rubin D.M. R. M.H. Finley D. A into the proteasome core PubMed Scopus Google Scholar). in has to this of residues M.R. Reed R.G. Rudack T. Schweitzer A. Beck F. Nagy I. Pfeifer G. Plitzko J.M. Baumeister W. Tomko R.J. Sakata E. Expanded coverage of the 26S proteasome conformational landscape reveals mechanisms of peptidase gating.Cell Rep. 2018; 24: 1301-1315.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). of this by either or in constitutively active CP M. M. A. Rubin D.M. R. M.H. Finley D. A into the proteasome core PubMed Scopus Google Scholar). The second feature of RP-mediated gate opening a unique clustering of residues at interface (8Förster A. Whitby F.G. Hill C.P. The pore of activated 20S proteasomes has an ordered 7-fold symmetric conformation.EMBO J. 2003; 22: 4356-4364Crossref PubMed Scopus (92) Google Scholar, A. Whitby F.G. Robinson H. Hill C.P. The of a activator complex and for Cell. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In a at the of the pore through that facilitate the open gate In the and which are in the closed to their in the open state. between subunits and α-subunits to at of these are by RP binding M.R. Reed R.G. Rudack T. Schweitzer A. Beck F. Nagy I. Pfeifer G. Plitzko J.M. Baumeister W. Tomko R.J. Sakata E. Expanded coverage of the 26S proteasome conformational landscape reveals mechanisms of peptidase gating.Cell Rep. 2018; 24: 1301-1315.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). However, the RP does not direct within the central and is by the RP this which is a for gate Here, we the mechanism of CP gate modulation by Pba1/2. the RP, Pba1/2 also the clustering the that this may be a of gate However, unlike the RP, Pba1 contacts within the central of the gate, disrupting the central by and Our data a unique to gate modulation by which likely exists only during proteasome We recently showed that proteasome assembly to Pba1/2 an open gate H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). A key feature of the open gate in CP is the clustering that occurs at the between neighboring at the from and from of which be at the center of the CP gate in the closed to a with and with the at seven within the CP We to Pba1/2 a clustering as the RP. We found that the in a manner CP for four of the seven The and In to the N terminus of not showed an that into the interior of the as we H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). In a of the N terminus of the critical also in an The of three interfaces, the the These suggest that binding of Pba1/2 key of RP-mediated gate opening and that may be a feature of CP gate Pba1 and directly with six of the seven clusters, these chaperones the open gate during CP assembly. A of Pba1 and contacts one of this to with the key of and the of the from the N terminus of Pba1 contacts the key of These to the of this and in Pba1 are with the in and from the HbYX motif of Pba1 is to in which likely the of the In of the terminus of Pba1 is in a complex arrangement of and with residues from and that appears to the terminus of Pba1 within the A of Pba1/2 to mature CP has E. K. Robinson H. D.M. Formosa T. Hill C.P. Structure of a proteasome complex for proteasome and Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, the contacts by HbYX motif of Pba1 are from in that the to and of E. K. Robinson H. D.M. Formosa T. Hill C.P. Structure of a proteasome complex for proteasome and Full Text Full Text PDF PubMed Scopus Google Scholar). Nevertheless, the arrangement of HbYX motif of Blm10 (7Sadre-Bazzaz K. Whitby F.G. Robinson H. Formosa T. Hill C.P. Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate opening.Mol. Cell. 2010; 37: 728-735Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar) is to the Pba1 arrangement both Blm10 and the is to a is between the and The N terminus of Pba1 also a at this a which N terminus of This is and further through between and both Pba1 and This arrangement appears to further promote the of the key of to facilitate The of at this is analogous to that of Pba1 with contacts the from with a direct to and The of appears to be further by its which in is to the further interacts with the and as in the of the terminus of Pba1 within the also appears to be through a of and These two are partially The feature for this appears to be the direct between the N terminus of Pba1 and the key of which directly the by Pba1 residues to to create a binding for with and at either of the The of also appears to the neighboring of from the of the The N termini of Pba1 and an interface that is the CP interior This not in the E. K. Robinson H. D.M. Formosa T. Hill C.P. Structure of a proteasome complex for proteasome and Full Text Full Text PDF PubMed Scopus Google Scholar) of that the residues of Pba1 The N terminus of Pba1 interacts with the key of and is at that the N terminus of is and the is the the clustering at six of the seven α-subunit interfaces. We to the of these interactions. The these can be by of is to proteasome in to K. Whitby F.G. A. Robinson H. Hill C.P. Structural for between the 20S proteasome and its 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, A.R. Kim Hochstrasser M. A 20S proteasome assembly requires a C-terminal HbYX motif for proteasomal PubMed Scopus Google Scholar). We the and which the and into the by protein upon to a that protein and These not of Pba1/2 in Pba1/2 bind to and is Pba1/2 to CP from to CP we the and into a which we showed has a CP assembly with of that contain Pba1/2 H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). their to bind CP that their their to their function within CP assembly. In the of the and the these key residues a at the center of the closed CP in in and and in has that is the or of this M.R. Reed R.G. Rudack T. Schweitzer A. Beck F. Nagy I. Pfeifer G. Plitzko J.M. Baumeister W. Tomko R.J. Sakata E. Expanded coverage of the 26S proteasome conformational landscape reveals mechanisms of peptidase gating.Cell Rep. 2018; 24: 1301-1315.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). the N terminus of Pba1 directly interacts with at the center of the gate A and and of which are to of the open gate state the key in is in in the in a manner that is from the open state of CP Pba1 directly the between and through its with and does this by with α-subunits for binding to the N terminus of the by the N terminus of we to the of its We to residues to from However, upon of we found that the in of of both Pba1 and We a this also in of of Pba1 and The of the we able to this in and with mature CP H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). these further analysis of these that the N terminus of Pba1 a critical in the or of the Pba1/2 we to the of these Pba1 by the of a of its residues be to the of Pba1 that mediate gate its N its C-terminal HbYX and the that the in and and however, be that this analysis to of the residues to either mediate Pba1/2 or mediate within Pba1 that likely facilitate the of the Our of CP assembly a unexpected structural arrangement the N terminus of Pba1 is through an open gate into the CP interior contacts α-subunits as as of the CP H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). the open gate conformation, the of Pba1/2 binding is from that of RP the pore is by the N terminus of Here, we the detailed mechanisms of CP gate opening by Pba1/2 and four of their Pba1/2 open the gate through a clustering to the RP, which in its detailed interactions. This is also by Blm10 and PA28, the that this may be a mechanism of gate we find that Pba1/2 directly six of the seven This is Pba1/2 are and insert at only two α-subunit interfaces, in to the RP, which has six subunits into the Our that the gate of Pba1/2 its HbYX motifs as residues both proteins to these interactions. the N terminus of Pba1 an in of these These are the of the ring the of Pba1/2 the we find that the N terminus of Pba1 directly the of residues from and that at the center of the The N terminus of Pba1 appears to this by for that maintain the gate in its closed state. The RP is not known to this and RP this remains likely in We that this mechanism in with the clustering to the gate however, we that direct binding to the central is not for gate opening, at for in as a of activating mature CP for H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). The Pba1 we are by a of at and the mammalian of Pba1 and Pba2, are thought to function to their only (9Hirano Y. Hendil K.B. Yashiroda H. Iemura S.I. Nagane R. Hioki Y. Natsume T. Tanaka K. Murata S. A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes.Nature. 2005; 437: 1381-1385Crossref PubMed Scopus (188) Google Scholar, 10Li X. Kusmierczyk A.R. Wong P. Emili A. Hochstrasser M. β-Subunit appendages promote 20S proteasome assembly by overcoming an Ump1-dependent checkpoint.EMBO J. 2007; 26: 2339-2349Crossref PubMed Scopus (114) Google and structural their with CP is an for be to mechanisms of gate Our data that the N terminus of Pba1 to both of gate opening The N terminus of Pba1 also appears to to the of Pba1/2 in the CP a is and the are A. A. of proteasome assembly and in and Rev. 2018; PubMed Scopus Google Scholar). However, the precise of that assembly remains Pba1/2 assembly with the of a second heterodimeric K. Y. Yashiroda H. H. A. Murata S. T. Tanaka K. T. K. as a in proteasome PubMed Scopus Google Scholar, R. R. A. 20S proteasome assembly is by two distinct of chaperones in and in Cell. 2007; 27: Full Text Full Text PDF PubMed Scopus Google Scholar, Cheng Li Y. Hochstrasser M. and 2017; PubMed Scopus Google Scholar). Interestingly, bind to the surface of the both Pba1/2 and are largely the of the ring E. K. Robinson H. D.M. Formosa T. Hill C.P. Structure of a proteasome complex for proteasome and Full Text Full Text PDF PubMed Scopus Google Scholar, H. T. K. T. H. T. S.I. M. E. Sakata E. K. A. Y. Murata S. K. of a complex that to the assembly of 20S PubMed Scopus Google Scholar). has as to the and are Our that the N terminus of Pba1 contacts the with with and to this be that Pba1/2 and of the with to the and Pba1/2 to the through the of However, its is to this In the that has to consists of to both and this not in in mammalian and only of or W. K. S. X. A. J. Yashiroda H. Murata S. proteasome assembly the core assembly in the 2018; PubMed Scopus Google Scholar). A related the of of both Pba1 and upon of the N terminus of We not the for this to the critical of this of A Pba1 Pba2, and that between the proteins are critical for their M.A. A. Roelofs J. of the proteasome core particle an that regulatory particle PubMed Scopus Google Scholar). with this Pba1 is in is X. Kusmierczyk A.R. Wong P. Emili A. Hochstrasser M. β-Subunit appendages promote 20S proteasome assembly by overcoming an Ump1-dependent checkpoint.EMBO J. 2007; 26: 2339-2349Crossref PubMed Scopus (114) Google Scholar). of the N terminus of Pba1 from interacts with is that the and Pba1 and through of their this these residues (especially residues for Pba1/2 the that the two proteins at sites. Structural Pba1/2 is not one is that the N terminus of Pba1 be to until Pba1/2 bind to the nascent The of Pba1/2 upon of the N terminus of Pba1 of the that the N terminus of Pba1 to CP Nevertheless, that is with the by the N terminus of Pba1 within the as as as with the assembly and the also H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google The of the CP gate in are the RP, Blm10, and of which The RP gate opening to facilitate protein Pba1/2 facilitate CP The function of Blm10 remains and a CP activator in as as its precise gate (7Sadre-Bazzaz K. Whitby F.G. Robinson H. Formosa T. Hill C.P. Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate opening.Mol. Cell. 2010; 37: 728-735Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, A. of 20S and proteasome Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the three complexes common mechanisms of gate the Pba1/2 unique in their to directly with the of residues from that the central of the gate and that are required to maintain the closed state. This which is in proteasome that the CP assume its closed gate until the release of Pba1/2 at the of assembly. The CP gate remains in this closed state until activated by the RP. are in and as R. G. J. in 2017; Google Scholar). and for are in and by by of their at in and H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google from in a R. G. J. in 2017; Google and in a of and the for in a from of by a as A. M.A. J. H.M. Y. Finley D. J. direct by the protein PubMed Scopus Google Scholar, H. A. J. function with protein Cell. 2017; PubMed Google Scholar). by by The M.A. A. Roelofs J. of the proteasome core particle an that regulatory particle PubMed Scopus Google H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google and from by and in or and at for the of CP a as H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). that are to CP from RP. CP by by with the The of proteasome has H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google Scholar). both of and for the analysis of of Pba1 residues H. S. E. O. I. T. to and in PubMed Scopus Google Scholar, G. G. H. F. E. I. T. data to protein J. 2013; Scopus Google Scholar). the proteasome H.M. S. M. Tian G. M.A. A. Roelofs J. Finley D. J. of assembly mechanisms of proteasome PubMed Scopus Google M. J. D. M. R. Structure of 20S proteasome from at PubMed Scopus Google M.R. Reed R.G. Rudack T. Schweitzer A. Beck F. Nagy I. Pfeifer G. Plitzko J.M. Baumeister W. Tomko R.J. Sakata E. Expanded coverage of the 26S proteasome conformational landscape reveals mechanisms of peptidase gating.Cell Rep. 2018; 24: 1301-1315.e5Abstract Full Text Full Text PDF PubMed Scopus (64) Google and (7Sadre-Bazzaz K. Whitby F.G. Robinson H. Formosa T. Hill C.P. Structure of a Blm10 complex reveals common mechanisms for proteasome binding and gate opening.Mol. Cell. 2010; 37: 728-735Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). This contains H. S. E. O. I. T. to and in PubMed Scopus Google Scholar, G. G. H. F. E. I. T. data to protein J. 2013; Scopus Google Scholar). The that of with the of this We Finley for and the H. M. S. and R. M. W. J. Y. and J. H. H. M. S. and J. H. H. M. S. and J. H. and This by the of and J. The is the of the and does not the of the of

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