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Research Themes Cell biology

Signaling: A Platform for Opposing Functions

SBKB [doi:10.1038/sbkb.2015.12]
Featured Article - May 2015
Short description: A modeled structure reveals the regulatory complexities of a TORC1-interacting complex.

In the absence of any prior structural information, integrative modeling was used to determine the molecular architecture of the SEA complex, a regulator of TORC1. Figure from ref. 1, ©2014 The American Society for Biochemistry and Molecular Biology.

The Tor1 complex (TORC1) integrates extracellular cues and mediates a cellular response to a variety of signals, including nutrients, hormones and stresses. Upon detection by TORC1, one environmental cue—nutrient limitation—activates a pathway leading to autophagy. Regulators of TORC1 have been identified, such as Npr2 and Npr3, that are part of a large, 1-MDa SEA complex also containing Sea1-4, Seh1 and Sec13. The SEA complex has several interesting features: it has elements that occur in proteins involved in trafficking and forming membrane coats; it has subunits that contain structural motifs found in GAPs and GEFs; and it localizes to the vacuolar membrane.

The groups of Dokudovskaya, Rout, Chait and Sali (PSI NYSGRC and NPCXstals Center) collaborated to determine the architecture of this complex through an integrative modeling approach that uses affinity purification and specific crosslinking information to map the interactions between subunits, even in the absence of any other structural information. The four-step modeling protocol yielded a unique solution, which indicated that there are two distinct subcomplexes. One, SEACIT, consists of Sea1 and Npr2-3; the other, SEACAT, consists of Sea2-4, Seh1 and Sec13. Sea4 and Seh1 are trimeric, and all other subunits are monomeric. The Sea3 protein links the two subcomplexes, and the β-propellers of the other SEACAT subunits appear to form a structural platform.

An analysis of the SEA complex interactome identified vacuolar membrane components and TORC1 itself. The relevance of these interactions was confirmed by localization studies showing that mutations in SEA complex components prevented localization of Tor1 to the vacuole membrane under limiting nutrient conditions. In addition, the mutants were impaired in their ability to induce autophagy and showed disrupted vacuole integrity. Conversely, inactivation of TORC1 caused degradation of the SEA complex, possibly initiated by the SEA proteins themselves.

The organization of the SEA complex suggests that it segregates opposing functions. The SEACIT subcomplex is responsible for inhibition of TORC1 function, as it contains putative GAP and GEF subunits. The SEACAT subcomplex, through its structure indicating a scaffold function, is expected to mediate the vacuolar membrane association and thereby activate TORC1. Future work should reveal how these contradictory activities of the SEA complex are coordinated.

Angela K. Eggleston

References

  1. R. Algret et al. Molecular architecture and function of the SEA complex, a modulator of the TORC1 pathway.
    Mol. Cell. Proteomics. 13, 2855-70 (2014). doi:10.1074/mcp.M114.039388

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