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• W1987782347 abstract "In this issue of Structure, Schwartz and coworkers present the structure of Nup120, a nucleoporin of the nuclear pore scaffold. The structure shows that, in contrast to earlier predictions, the nucleoporins have a larger fold repertoire than expected. In this issue of Structure, Schwartz and coworkers present the structure of Nup120, a nucleoporin of the nuclear pore scaffold. The structure shows that, in contrast to earlier predictions, the nucleoporins have a larger fold repertoire than expected. The structure determination of the nuclear pore complex (NPC) at atomic resolution is still one of the greatest challenges of molecular biology. One of the major obstacles is the dynamic nature of a large part of the protein inventory of the nuclear pore, called nucleoporins. Only a minor part of the pore is composed of more or less stably associated, scaffold nucleoporins that establish its octagonal structure. Thus, any attempts at structure determination of the NPC have to focus—at least initially—on those structural nucleoporins. Due to the low sequence conservation between orthologous nucleoporins, structure determination is hampered by the need to perform extensive searches for fragments of nucleoporins suitable for expression and crystallization. In spite of those problems, a number of very important scaffold nucleoporin structures have been solved recently by means of X-ray crystallography. Those studies concerned the two major scaffold complexes of the nuclear pore: the Nup84 and the Nic96 complex (yeast nomenclature) (Lutzmann et al., 2002Lutzmann M. Kunze R. Buerer A. Aebi U. Hurt E. EMBO J. 2002; 21: 387-389Crossref PubMed Scopus (167) Google Scholar, Grandi et al., 1995Grandi P. Schlaich N. Tekotte H. Hurt E.C. EMBO J. 1995; 14: 76-87Crossref PubMed Scopus (131) Google Scholar). Prior to high-resolution crystal structures, the Nup84 complex was extensively biochemically characterized (Siniossoglou et al., 2000Siniossoglou S. Lutzmann M. Santos-Rosa H. Leonard K. Mueller S. Aebi U. Hurt E. J. Cell Biol. 2000; 149: 41-53Crossref PubMed Scopus (139) Google Scholar) and its structure investigated by electron microscopy (Lutzmann et al., 2002Lutzmann M. Kunze R. Buerer A. Aebi U. Hurt E. EMBO J. 2002; 21: 387-389Crossref PubMed Scopus (167) Google Scholar). Combination of the high-resolution structures with an improved low-resolution electron microscopic map recently led to a more detailed view of the Nup84 complex architecture (Figure 1A) (Kampmann and Blobel, 2009Kampmann M. Blobel G. Nat. Struct. Mol. Biol. 2009; 16: 782-788Crossref PubMed Scopus (87) Google Scholar). The first substructures of this complex, Nup85•Seh1 (Brohawn et al., 2008Brohawn S.G. Leksa N.C. Spear E.D. Rajashankar K.R. Schwartz T.U. Science. 2008; 322: 1369-1373Crossref PubMed Scopus (153) Google Scholar, Debler et al., 2008Debler E. Ma Y. Seo H.-S. Hsia K.-C. Noriega T.R. Blobel G. Hoelz A. Mol. Cell. 2008; 32: 815-826Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar), Nup145C•Sec13 (Hsia et al., 2007Hsia K.-C. Stavropoulos P. Blobel G. Hoelz A. Cell. 2007; 131: 1313-1326Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar), Nup107(= Nup84 in yeast)•Nup133 (Boehmer et al., 2008Boehmer T. Jeudy S. Berke I.C. Schwartz T.U. Mol. Cell. 2008; 30: 721-731Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar), and the β-propeller domain of Nup133 (Berke et al., 2004Berke I.C. Boehmer T. Blobel G. Schwartz T.U. J. Cell Biol. 2004; 167: 571-579Crossref Scopus (88) Google Scholar) were determined by the groups of T. Schwartz and G. Blobel. Nup85 and Nup145C in the Nup85•Seh1 and the Nup145C•Sec13 complexes are composed of an α-helical domain that provides an N-terminal extension, which, surprisingly, supplies one blade of the 7-bladed β−propellers of Seh1 and Sec13 in trans and turned out to be structurally related to the Sec31•Sec13 complex of the outer coat of COPII vesicles, in spite of a very low sequence homology. They were thus termed “ancestral coatomer elements” (ACE1) by the Schwartz group (Brohawn et al., 2008Brohawn S.G. Leksa N.C. Spear E.D. Rajashankar K.R. Schwartz T.U. Science. 2008; 322: 1369-1373Crossref PubMed Scopus (153) Google Scholar). Indeed, an evolutionary relationship of the NPC to vesicle coating complexes was already proposed due to the results of secondary structure predictions of nucleoporins (Devos et al., 2004Devos D. Dokudovskaya S. Alber F. Williams R. Chait B.T. Sali A. Rout M.P. PLoS Biol. 2004; 2: e380Crossref PubMed Scopus (306) Google Scholar). This current study describes the structure of the N-terminal fragment 1-757 of yeast Nup120, the last major constituent missing from the Nup84 complex. The authors showed, via gel filtration experiments, that Nup120 is located at the hub of the Y-shaped Nup84 complex where it forms one of the short arms of the Y (Figure 1A) (Brohawn et al., 2008Brohawn S.G. Leksa N.C. Spear E.D. Rajashankar K.R. Schwartz T.U. Science. 2008; 322: 1369-1373Crossref PubMed Scopus (153) Google Scholar, Leksa et al., 2009Leksa N.C. Brohawn S.G. Schwartz T.U. Structure. 2009; 17 (this issue): 1082-1091Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). Interestingly, Nup120 does not show the assumed topology of an N-terminal β−propeller and a subsequent C-terminal α-helical domain, but instead the β−propeller contains a very unusual insertion of an α-helical bundle that forms the complete α-helical domain together with the C-terminal α-helical domain that follows the β-propeller. This unexpected result further strengthens the point that nucleoporin folds show much larger variations than initially expected from the secondary structure predictions (Devos et al., 2004Devos D. Dokudovskaya S. Alber F. Williams R. Chait B.T. Sali A. Rout M.P. PLoS Biol. 2004; 2: e380Crossref PubMed Scopus (306) Google Scholar). The complete protein seems to form a rigid and compact oval shape. The missing C terminus (predicted to be α-helical) was shown in this work to be important for the integration of Nup120 into the Nup84 complex and into the NPC, although it is not clear if it is attached either in a rigid or in a flexible way. The increasing number of solved structures, together with the structure predictions (Devos et al., 2004Devos D. Dokudovskaya S. Alber F. Williams R. Chait B.T. Sali A. Rout M.P. PLoS Biol. 2004; 2: e380Crossref PubMed Scopus (306) Google Scholar), point to β−propellers as a general feature of nucleoporins that are most likely universally employed to mediate contacts between the nucleoporins. Using the homologies to the protein interactions known from coated vesicles, two models were proposed for the arrangement of the scaffold complexes in the nuclear pore: the “lattice” model by Schwartz and coworkers (Figure 1B) (Brohawn et al., 2008Brohawn S.G. Leksa N.C. Spear E.D. Rajashankar K.R. Schwartz T.U. Science. 2008; 322: 1369-1373Crossref PubMed Scopus (153) Google Scholar), and the “concentric cylinder” model by the Blobel group (Figure 1C) (Hsia et al., 2007Hsia K.-C. Stavropoulos P. Blobel G. Hoelz A. Cell. 2007; 131: 1313-1326Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). A major difference between those models is the orientation of the heptameric Nup84 complexes relative to each other; the “concentric cylinder” model is based on the observation that Sec13•Nup145C heterodimers pack as hetero-octamers in the crystal, thus forming a slightly curved rod. This rod would form one of the columns of the nuclear pore parallel to the axis of the central pore channel, with the heptameric complexes oriented with their long axis in the plane of the nuclear envelope and forming four stacked rings in a head-to-tail fashion (Figure 1C) (Hsia et al., 2007Hsia K.-C. Stavropoulos P. Blobel G. Hoelz A. Cell. 2007; 131: 1313-1326Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). In contrast, the “lattice” model (Figure 1B) was proposed in closer analogy to the COPII vesicle coat, with Nup84 complex building blocks forming a polygonal mesh with a much looser packing, in comparison to the “concentric cylinder” model (Figures 1B and 1C). More recent biochemical data showed that an important Nup84 binding site of Nup145C would be concealed by the proposed Nup145C•Sec13 lattice contacts, thus arguing against the “concentric cylinder” model (Brohawn et al., 2008Brohawn S.G. Leksa N.C. Spear E.D. Rajashankar K.R. Schwartz T.U. Science. 2008; 322: 1369-1373Crossref PubMed Scopus (153) Google Scholar). The structure of Nup120 presented in this study also sheds light on an additional question whether the Nup84 complex directly contacts the nuclear membrane or not: A predicted membrane-inserting ALPS motif (that is also present in the structure of the Nup133 fragment (Berke et al., 2004Berke I.C. Boehmer T. Blobel G. Schwartz T.U. J. Cell Biol. 2004; 167: 571-579Crossref Scopus (88) Google Scholar) and is in an exposed position there) is hidden inside the core of Nup120. It is very unlikely that it could swing out and interact with the membrane. Thus, the authors deem it more likely that the Nup84 complex does not directly interact with the pore membrane (in analogy to the outer COPII coat), but that it is anchored by another set of proteins, one candidate being the essential transmembrane nucleoporin Ndc1. In the double-layered COPII coat recently analyzed by electron cryomicroscopy (Stagg et al., 2008Stagg S.M. LaPointe P. Razvi A. Gürkan C. Potter C.S. Carragher B. Balch W.E. Cell. 2008; 134: 474-484Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar), a layer of Sec23•Sec24 heterodimers mediates the contact between the Sec13•Sec31 vertices and specific transmembrane proteins in the membrane of the coated vesicle. The study by Stagg et al., 2008Stagg S.M. LaPointe P. Razvi A. Gürkan C. Potter C.S. Carragher B. Balch W.E. Cell. 2008; 134: 474-484Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar revealed a remarkable flexibility in the angles of the COPII lattice, accommodating a wide range of curvatures and thus allowing for vesicle diameters from 60 to 100 nm. By further extrapolating this observation, the flexible vertices might make it possible for the COPII lattice to cover even a planar surface. Furthermore, one can imagine that this flexible system could have relatively easily adapted to coat the curved membrane wall of the nuclear pore with its diameter of approx. 100 nm. A major problem with those models is the observation that the intra-subunit interactions between the members of the Nup84 complex seem to be quite strong, but the affinities determined between different Nup84 complexes or between Nup84 complexes and other nucleoporins are quite weak. So it is difficult to envision how the Nup84 complexes can form the clearly defined octameric structure of the nuclear pore, and more research is needed to solve this puzzle. The authors themselves state that without more detailed data on interactions between the NPC subcomplexes any NPC assembly model has to be interpreted with due caution. Potential candidates for mediating the intercomplex contacts are, again in analogy to the COPII coat, the β−propellers of Nup120, Nup133 and Nup85. It remains to be shown if it is possible to reconstitute a NPC scaffold in vitro like it has been done for the COPII coat (Fath et al., 2007Fath S. Mancias J.D. Bi X. Goldberg J. Cell. 2007; 129: 1325-1336Abstract Full Text Full Text PDF PubMed Scopus (203) Google Scholar, Stagg et al., 2008Stagg S.M. LaPointe P. Razvi A. Gürkan C. Potter C.S. Carragher B. Balch W.E. Cell. 2008; 134: 474-484Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar) which would be the ultimate test for any model. The Structure of the Scaffold Nucleoporin Nup120 Reveals a New and Unexpected Domain ArchitectureLeksa et al.StructureJuly 2, 2009In BriefNucleocytoplasmic transport is mediated by nuclear pore complexes (NPCs), enormous protein assemblies residing in circular openings in the nuclear envelope. The NPC is modular, with transient and stable components. The stable core is essentially built from two multiprotein complexes, the Y-shaped heptameric Nup84 complex and the Nic96 complex, arranged around an eightfold axis. We present the crystal structure of Nup1201-757, one of the two short arms of the Y-shaped Nup84 complex. The protein adopts a compact oval shape built around a novel bipartite α-helical domain intimately integrated with a β-propeller domain. Full-Text PDF Open Archive" @default.
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• W1987782347 title "Nup120: One More Piece in the NPC Puzzle" @default.
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