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Integrative structure and functional anatomy of a nuclear pore complex
Nuclear pore complexes play central roles as gatekeepers of RNA and protein transport between the cytoplasm and nucleoplasm. However, their large size and dynamic nature have impeded a full structural and functional elucidation. Here we determined the structure of the entire 552-protein nuclear pore complex of the yeast
Saccharomyces cerevisiae
at sub-nanometre precision by satisfying a wide range of data relating to the molecular arrangement of its constituents. The nuclear pore complex incorporates sturdy diagonal columns and connector cables attached to these columns, imbuing the structure with strength and flexibility. These cables also tie together all other elements of the nuclear pore complex, including membrane-interacting regions, outer rings and RNA-processing platforms. Inwardly directed anchors create a high density of transport factor-docking Phe-Gly repeats in the central channel, organized into distinct functional units. This integrative structure enables us to rationalize the architecture, transport mechanism and evolutionary origins of the nuclear pore complex.
The structure of the yeast nuclear pore complex, determined at sub-nanometre precision using an integrative approach that combines a wide range of data, reveals details of its architecture, transport mechanism and evolutionary origins.
Structure of yeast nuclear pore complex
Nuclear pore complexes (NPCs) are the gateways for the transport of RNA and proteins into and out of the nucleus. Although previous work has provided structural insights into parts of NPCs, getting a full picture of these complexes has proved difficult owing to their large size and dynamic nature. A multidisciplinary team of researchers now report the structure of the entire 552-protein NPC of the yeast at a sub-nanometre level using an integrative approach including mass spectrometry, cryo-electron tomography and chemical crosslinking. The structure provides a detailed view of the functional elements of the NPC and clarifies its architecture, mechanism of action and evolutionary origins.
Journal Article
The molecular architecture of the nuclear pore complex
Nuclear pore complexes (NPCs) are proteinaceous assemblies of approximately 50 MDa that selectively transport cargoes across the nuclear envelope. To determine the molecular architecture of the yeast NPC, we collected a diverse set of biophysical and proteomic data, and developed a method for using these data to localize the NPC’s 456 constituent proteins (see the accompanying paper). Our structure reveals that half of the NPC is made up of a core scaffold, which is structurally analogous to vesicle-coating complexes. This scaffold forms an interlaced network that coats the entire curved surface of the nuclear envelope membrane within which the NPC is embedded. The selective barrier for transport is formed by large numbers of proteins with disordered regions that line the inner face of the scaffold. The NPC consists of only a few structural modules that resemble each other in terms of the configuration of their homologous constituents, the most striking of these being a 16-fold repetition of ‘columns’. These findings provide clues to the evolutionary origins of the NPC.
Gatekeeper for the Nucleus
The nuclear pore complex plays a crucial role in the cell, as gatekeeper for traffic between the cytoplasm and the interior of the nucleus. It is a large supramolecular complex made up of multiple copies of about 30 different proteins — 456 protein molecules in all. Cell biologists would love to know how each of the pore molecules are placed, but so far this has eluded conventional structural studies. Now, a new proteomics-based technique has provided a detailed view of the architecture of the yeast nuclear pore complex. Half of the complex is made of a core scaffold forming a network coating the surface of the nuclear envelope membrane within which the complex is embedded. The selective transport barrier is formed by the many proteins lining the inner face of the scaffold. Despite its size, there are only a few structural modules in the complex; this underlying simplicity provides possible pointers to an evolutionary origin from a 'primordial' nuclear pore complex. In the cover graphic, the 100-nm diameter pores are shown in the silver-grey nuclear envelope.
Journal Article
Determining the architectures of macromolecular assemblies
To understand the workings of a living cell, we need to know the architectures of its macromolecular assemblies. Here we show how proteomic data can be used to determine such structures. The process involves the collection of sufficient and diverse high-quality data, translation of these data into spatial restraints, and an optimization that uses the restraints to generate an ensemble of structures consistent with the data. Analysis of the ensemble produces a detailed architectural map of the assembly. We developed our approach on a challenging model system, the nuclear pore complex (NPC). The NPC acts as a dynamic barrier, controlling access to and from the nucleus, and in yeast is a 50 MDa assembly of 456 proteins. The resulting structure, presented in an accompanying paper, reveals the configuration of the proteins in the NPC, providing insights into its evolution and architectural principles. The present approach should be applicable to many other macromolecular assemblies.
Gatekeeper for the Nucleus
The nuclear pore complex plays a crucial role in the cell, as gatekeeper for traffic between the cytoplasm and the interior of the nucleus. It is a large supramolecular complex made up of multiple copies of about 30 different proteins — 456 protein molecules in all. Cell biologists would love to know how each of the pore molecules are placed, but so far this has eluded conventional structural studies. Now, a new proteomics-based technique has provided a detailed view of the architecture of the yeast nuclear pore complex. Half of the complex is made of a core scaffold forming a network coating the surface of the nuclear envelope membrane within which the complex is embedded. The selective transport barrier is formed by the many proteins lining the inner face of the scaffold. Despite its size, there are only a few structural modules in the complex; this underlying simplicity provides possible pointers to an evolutionary origin from a 'primordial' nuclear pore complex. In the cover graphic, the 100-nm diameter pores are shown in the silver-grey nuclear envelope.
Journal Article
Components of Coated Vesicles and Nuclear Pore Complexes Share a Common Molecular Architecture
Numerous features distinguish prokaryotes from eukaryotes, chief among which are the distinctive internal membrane systems of eukaryotic cells. These membrane systems form elaborate compartments and vesicular trafficking pathways, and sequester the chromatin within the nuclear envelope. The nuclear pore complex is the portal that specifically mediates macromolecular trafficking across the nuclear envelope. Although it is generally understood that these internal membrane systems evolved from specialized invaginations of the prokaryotic plasma membrane, it is not clear how the nuclear pore complex could have evolved from organisms with no analogous transport system. Here we use computational and biochemical methods to perform a structural analysis of the seven proteins comprising the yNup84/vNup107-160 subcomplex, a core building block of the nuclear pore complex. Our analysis indicates that all seven proteins contain either a beta-propeller fold, an alpha-solenoid fold, or a distinctive arrangement of both, revealing close similarities between the structures comprising the yNup84/vNup107-160 subcomplex and those comprising the major types of vesicle coating complexes that maintain vesicular trafficking pathways. These similarities suggest a common evolutionary origin for nuclear pore complexes and coated vesicles in an early membrane-curving module that led to the formation of the internal membrane systems in modern eukaryotes.
Journal Article
Simple Fold Composition and Modular Architecture of the Nuclear Pore Complex
The nuclear pore complex (NPC) consists of multiple copies of ≈30 different proteins [nucleoporins (nups)], forming a channel in the nuclear envelope that mediates macromolecular transport between the cytosol and the nucleus. With <5% of the nup residues currently available in experimentally determined structures, little is known about the detailed structure of the NPC. Here, we use a combined computational and biochemical approach to assign folds for ≈95% of the residues in the yeast and vertebrate nups. These fold assignments suggest an underlying simplicity in the composition and modularity in the architecture of all eukaryotic NPCs. The simplicity in NPC composition is reflected in the presence of only eight fold types, with the three most frequent folds accounting for ≈85% of the residues. The modularity in NPC architecture is reflected in its hierarchical and symmetrical organization that partitions the predicted nup folds into three groups: the transmembrane group containing transmembrane helices and a cadherin fold, the central scaffold group containing β-propeller and α-solenoid folds, and the peripheral FG group containing predominantly the FG repeats and the coiled-coil fold. Moreover, similarities between structures in coated vesicles and those in the NPC support our prior hypothesis for their common evolutionary origin in a progenitor protocoatomer. The small number of predicted fold types in the NPC and their internal symmetries suggest that the bulk of the NPC structure has evolved through extensive motif and gene duplication from a simple precursor set of only a few proteins.
Journal Article
Tech Tools to Connect with Citizens
From simple web pages detailing agency expenses came a comprehensive resource for citizens with information, complete with visual tools, downloadable data sets, and a dashboard on economic development spending by fund.1 Meanwhile, the State of Georgia gives citizens access to information on state spending and revenues through open.georgia.gov, which is regularly updated by various state agencies. [...]with good reason: research confirms citizens support government use of sharing platforms and also points to opportunities to enhance citizen perceptions of government.2 Good examples include: * Municipal governments' usage of the mobile app SeeClickFix to report non-emergency issues. * Riverside County, California, employees' use of Microsoft business intelligence data analytics to streamline government spending and increase transparency. * The DC Public Library and DC Water's Twitter feeds with assorted public service announcements. * The City of Lafayette, Louisiana's solution, built with Microsoft products and the city's phone systems to promote better customer service. * North Carolina Department of Transportation's use of Instagram accounts for updates on individual public infrastructure projects. Social media can be a powerful tool for raising awareness and encouraging citizen participation.
Journal Article
Distinctive and Shared Health Needs of Minority Communities by Immigrant Status
To identify distinct and shared health barriers, priorities, and desired information within minority communities by immigrant status. Health needs assessment surveys were conducted at three different health fairs in San Antonio from October 22, 2022 to January 14, 2023. Data was compared using descriptive statistics by immigration status. Among 59 US-born and 55 non-US-born respondents, nutrition and mental health were the highest health priorities. Time was a greater barrier among US-born respondents (
p
=.007) while lack of insurance was a greater barrier among non-US-born respondents (
p
=.008). Although the US-born group had higher rates of insurance (74%) compared to the non-US-born group (64%) (
p
=.019), both had similar rates of having a primary care provider. The US-born group had a higher number of emergency department (ED) visits (
p
=.030). There are multiple commonalities and differences among health needs in ethnically diverse communities in South Texas. Future health interventions targeted toward minority communities should consider nutrition and mental health while also addressing unique barriers. Multiple factors such as access to free clinics, personal safety, language, and health insurance status are integral to minority group health.
Journal Article