Expanded Interactome of the Intrinsically Disordered Protein Dss1.

Dss1 (also known as Sem1) is a conserved, intrinsically disordered protein with a remarkably broad functional diversity. It is a proteasome subunit but also associates with the BRCA2, RPA, Csn12-Thp1, and TREX-2 complexes. Accordingly, Dss1 functions in protein degradation, DNA repair, transcription, and mRNA export. Here in Schizosaccharomyces pombe, we expand its interactome further to include eIF3, the COP9 signalosome, and the mitotic septins. Within its intrinsically disordered ensemble, Dss1 forms a transiently populated C-terminal helix that dynamically interacts with and shields a central binding region. The helix interfered with the interaction to ATP-citrate lyase but was required for septin binding, and in strains lacking Dss1, ATP-citrate lyase solubility was reduced and septin rings were more persistent. Thus, even weak, transient interactions within Dss1 may dynamically rewire its interactome.

DSS1/Sem1, a Multifunctional and Intrinsically Disordered Protein.

DSS1/Sem1 is a versatile intrinsically disordered protein. Besides being a bona fide subunit of the 26S proteasome, DSS1 associates with other protein complexes, including BRCA2-RPA, involved in homologous recombination; the Csn12-Thp3 complex, involved in RNA splicing; the integrator, involved in transcription; and the TREX-2 complex, involved in nuclear export of mRNA and transcription elongation. As a subunit of the proteasome, DSS1 functions both in complex assembly and possibly as a ubiquitin receptor. Here, we summarise structural and functional aspects of DSS1/Sem1 with particular emphasis on its multifunctional and disordered properties. We suggest that DSS1/Sem1 can act as a polyanionic adhesive to prevent nonproductive interactions during construction of protein assemblies, uniquely employing different structures when associating with the diverse multisubunit complexes.

Protein quality control in the nucleus.

In their natural environment, cells are regularly exposed to various stress conditions that may lead to protein misfolding, but also in the absence of stress, misfolded proteins occur as the result of mutations or failures during protein synthesis. Since such partially denatured proteins are prone to aggregate, cells have evolved several elaborate quality control systems to deal with these potentially toxic proteins. First, various molecular chaperones will seize the misfolded protein and either attempt to refold the protein or target it for degradation via the ubiquitin-proteasome system. The degradation of misfolded proteins is clearly compartmentalized, so unique degradation pathways exist for misfolded proteins depending on whether their subcellular localization is ER/secretory, mitochondrial, cytosolic or nuclear. Recent studies, mainly in yeast, have shown that the nucleus appears to be particularly active in protein quality control. Thus, specific ubiquitin-protein ligases located in the nucleus, target not only misfolded nuclear proteins, but also various misfolded cytosolic proteins which are transported to the nucleus prior to their degradation. In comparison, much less is known about these mechanisms in mammalian cells. Here we highlight recent advances in our understanding of nuclear protein quality control, in particular regarding substrate recognition and proteasomal degradation.