Assessing the Reconstruction of Macro-molecular Assemblies: the Example of the Nuclear Pore Complex

Frédéric Cazals 1, * Tom Dreyfus 1
* Corresponding author
1 ABS - Algorithms, Biology, Structure
CRISAM - Inria Sophia Antipolis - Méditerranée
Abstract : The reconstruction of large protein assemblies is a major challenge due to their plasticity and due to the flexibility of the proteins involved. An emerging trend to cope with these uncertainties consists of performing the reconstruction by integrating experimental data from several sources, a strategy recently used to propose qualitative reconstructions of the Nuclear Pore Complex. Yet, the absence of clearly identified canonical reconstructions and the lack of quantitative assessment with respect to the experimental data are detrimental to the mechanistic exploitation of the results. To leverage such reconstructions, this work proposes a modeling framework inherently accommodating uncertainties, and allowing a precise assessment of the reconstructed models. We make three contributions. First, we introduce {\em toleranced models} to accommodate the positional and conformational uncertainties of protein instances within large assemblies. A toleranced model is a continuum of geometries whose distinct topologies can be enumerated, and mining stable complexes amidst this finite set hints at important structures in the assembly. Second, we present a panoply of tools to perform a multi-scale topological, geometric, and biochemical assessment of the complexes associated to a toleranced model, at the assembly and local levels. At the assembly level, we assess the prominence of contacts and the quality of the reconstruction, in particular w.r.t symmetries. At the local level, the complexes encountered in the toleranced model are used to confirm / question / suggest protein contacts within a known 3D template known at atomic resolution. Third, we apply our machinery to the NPC for which we (i) report prominent contacts uncovering sub-complexes of the NPC, (ii) explain the closure of the two rings involving 16 copies of the $Y$-complex, and (iii) develop a new 3D template for the $T$-complex. These contributions should prove instrumental in enhancing the reconstruction of assemblies, and in selecting the models which best comply with experimental data.
Liste complète des métadonnées

Cited literature [30 references]  Display  Hide  Download

https://hal.inria.fr/inria-00559117
Contributor : Frederic Cazals <>
Submitted on : Wednesday, March 2, 2011 - 10:37:48 PM
Last modification on : Saturday, September 17, 2016 - 1:36:52 AM
Document(s) archivé(s) le : Saturday, December 3, 2016 - 11:18:05 PM

File

RR-7513-v2.pdf
Files produced by the author(s)

Identifiers

  • HAL Id : inria-00559117, version 2

Collections

Citation

Frédéric Cazals, Tom Dreyfus. Assessing the Reconstruction of Macro-molecular Assemblies: the Example of the Nuclear Pore Complex. [Research Report] RR-7513, INRIA. 2011. 〈inria-00559117v2〉

Share

Metrics

Record views

273

Files downloads

484