Molecular architecture of the inner ring scaffold of the human nuclear pore complex - PubMed (original) (raw)

. 2016 Apr 15;352(6283):363-5.

doi: 10.1126/science.aaf0643.

Shyamal Mosalaganti 1, Alexander von Appen 1, Roman Teimer 2, Amanda L DiGuilio 3, William Wan 1, Khanh Huy Bui 4, Wim J H Hagen 1, John A G Briggs 5, Joseph S Glavy 3, Ed Hurt 2, Martin Beck 5

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Molecular architecture of the inner ring scaffold of the human nuclear pore complex

Jan Kosinski et al. Science. 2016.

Abstract

Nuclear pore complexes (NPCs) are 110-megadalton assemblies that mediate nucleocytoplasmic transport. NPCs are built from multiple copies of ~30 different nucleoporins, and understanding how these nucleoporins assemble into the NPC scaffold imposes a formidable challenge. Recently, it has been shown how the Y complex, a prominent NPC module, forms the outer rings of the nuclear pore. However, the organization of the inner ring has remained unknown until now. We used molecular modeling combined with cross-linking mass spectrometry and cryo-electron tomography to obtain a composite structure of the inner ring. This architectural map explains the vast majority of the electron density of the scaffold. We conclude that despite obvious differences in morphology and composition, the higher-order structure of the inner and outer rings is unexpectedly similar.

Copyright © 2016, American Association for the Advancement of Science.

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Figures

Fig. 1.

Fig. 1.. Composite structure of the human NPC.

(A) Overview of the composite structure of the entire NPC, in which previous structural assignments in the outer rings (9, 13) are represented together with the assignments in the IR that were undertaken in this study (details are shown in fig. S2). Unassigned density is shown in cyan; the nuclear ring is facing up. (B) Zoomed-in view of the IR region framed in (A). High-resolution structures (colored ribbons) are shown in the context of the tomographic map (transparent isosurface). (C) Conceptual outline of the NPC architecture. Inner (gray) and outer (orange) copies of the Ycomplex (top and bottom) and the IR core module (middle) are shown in comparison.The configurations of the outer and inner copies of the IR core module are shown enlarged on the right. FG repeat domains can readily reach out into the central channel (F, phenylalanine; G, glycine).

Fig. 2.

Fig. 2.. Cross-linking mass spectrometry confirms intraand inter-subcomplex interactions of the IR architecture.

(A) Primary schematic of the IR proteins, showing the cross-links obtained by mass spectrometry. Inter-protein cross-links are shown in black, intra-protein links in light purple, and homodimeric cross-links (linking the same residues of a protein) in red. For clarity, Nup53 is not drawn to scale. Colored areas within the primary structures mark domains and motifs as individually labeled (residues are indicated below). A larger version is shown in fig. S6, and table S1 provides details on the cross-link data sets. The cross-links [blue lines in (B) to (D)] confirm specific features suggested by the composite structure, such as (B) head-to-tail arrangement of the inner and outer copy of Nup93, (C) interaction between Nup93 and Nup205, and (D) positioning of the Nup54 ferredoxin-like domain within the Nup62 complex.

Fig. 3.

Fig. 3.. Simple and highly similar organizational principles govern the architecture of the inner and outer rings of the NPC.

(A) Schematic representation of the branching motif formed by the different heterodimers. (B) Structural similarity of the Nup155-Nup93 dimer to the Nup107-Nup133 and Nup120-Nup85 dimers. The structures are shown in low-resolution representation within the corresponding segments of the tomographic map. Homologous Nups are colored identically. (C) Arrangement of the branching motifs within the NPC membrane-binding coat [homologous Nups are colored as in (B)]. (D) Schematic of the human NPC architecture (details are shown in figs. S9 to S11). Trailing lines indicate FG repeats.

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