The nuclear pore complex (NPC) is a large, modular protein assembly that principally regulates nucleocytoplasmic transport in all eukaryotes. The ~60-120MDa NPC is a modular assembly of multiple copies of ~30 distinct proteins that are arranged into sub-complexes. The entire NPC is not amenable to high- resolution structural studies, due to its large size and intrinsic flexibility. However, using a divide and conquer approach we tackle this problem by taking advantage of the modular nature of the NPC and obtaining high- resolution structures of individual sub-complexes. As a first step towards understanding the detailed organization of the NPC, we propose to solve high-resolution structures of the NPC structural scaffold Y and Nic96 complex and to characterize their inter-complex interactions. Our preliminary results present a high-resolution complete composite structure of the Y-complex. We compare our results to previous low-resolution studies and highlight the importance of high-resolution structures of the scaffold sub-complexes. Previous structural studies have shown a strong evolutionary relationship between a number of Y and Nic96 complex components. Thus, by leveraging our experience with the structurally well-characterized Y complex, this proposal will focus on investigating the biochemical characteristics of the evolutionarily similar but less investigated Nic96 complex and elucidate its high-resolution structure. Concurrently, the inter-complex interactions between the Y and Nic96 complex will be established as a first step towards understanding their function and organization into the NPC. A detailed structure of the Nic96 complex and its interplay with the Y-complex will uncover the structural basis for the function of the NPC and the various diseases associated with scaffold components.

Public Health Relevance

The nuclear pore complex (NPC) is the multi-protein macromolecular assembly responsible for regulated transport of molecules across the nuclear envelope. Despite recent progress in the structural characterization of the NPC, the lack of high-resolution structural details of the NPC has hampered the understanding of the transport mechanism and the various pathologies and human diseases associated with deletions or mutations in constituents. The structural and biochemical studies presented in this proposal aims to characterize in detail the two principal NPC structural scaffold sub-complexes, the Y and Nic96 complex.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Sakalian, Michael
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Kelley, Kotaro; Knockenhauer, Kevin E; Kabachinski, Greg et al. (2015) Atomic structure of the Y complex of the nuclear pore. Nat Struct Mol Biol 22:425-431