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Review
. 2014 Jul 9;114(13):6806-43.
doi: 10.1021/cr4007329. Epub 2014 Apr 4.

Disordered proteinaceous machines

Monika Fuxreiter  1 , Ágnes Tóth-Petróczy, Daniel A Kraut, Andreas Matouschek, Roderick Y H Lim, Bin Xue, Lukasz Kurgan, Vladimir N Uversky
Affiliations
Review

Disordered proteinaceous machines

Monika Fuxreiter et al. Chem Rev. .

Erratum in

  • Correction to disordered proteinaceous machines.
    Fuxreiter M, Tóth-Petróczy Á, Kraut DA, Matouschek A, Lim RY, Xue B, Kurgan L, Uversky VN. Fuxreiter M, et al. Chem Rev. 2015 Apr 8;115(7):2780. doi: 10.1021/acs.chemrev.5b00150. Epub 2015 Mar 26. Chem Rev. 2015. PMID: 25811425 Free PMC article. No abstract available.
No abstract available

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Figures

Figure 1
Figure 1
Different classification types of protein–protein complexes. (A) Composition and geometry-based classifications. Complexes can be assembled from identical (a) and different subunits (b). Different types of monomers are shown by different shades of yellow and blue colors. Interactions leading to homo-oligomers are shown by arrows of the corresponding color. Interactions leading to the hetero-oligomers are shown by green arrows. Homodimers associate isologously. Interfaces of the dimers located at the center of homotetramers are also formed isologously, whereas all of the interfaces in the hetero-oligomers and the interfaces formed between the central homodimers and side-added monomers are formed heterologously. (B) Lifetime-based classification of oligomers. Complexes can be of transient (a), permanent nonobligate (b), or permanent obligate (c) nature. Formation of the permanent obligate complex is accompanied by the global folding of protomers. Hero-dimers and homologous transitions are shown for simplicity. (C) Folding-based classification. Protein complexes can be formed in a three-state mechanism (a), where protein folding and binding happen as two independent and subsequent steps. Alternatively, some proteins are formed in a two-state manner (b), where folding and binding occur simultaneously. (D) The per-residue surface area versus the per-residue interface area plot to discriminate between the three-state and two-state complexes. Here, the results of the computational disassembly of the eukaryotic ribosome (PDB ID: 3U5C and 3U5E) are shown. Surface and interface area normalized by the number of residues in each chain for the ribosomal proteins were estimated as described in ref (64). Proteins of the 40S and 60S subunits are shown by red and blue circles, respectively. A boundary separating ordered and disordered complexes is shown as a black dashed line.
Figure 2
Figure 2
Two models illustrating binding between an IDP and an ordered partner with a “hidden” binding site. (A) A simple model of interaction with one binding intermediate. (B) A more complex model with two sequential binding intermediates.
Figure 3
Figure 3
Model of the binding chain reaction. See explanations in the text.
Figure 4
Figure 4
Schematic representation of Mediator subunits: Head (orange), Middle (green), Tail (yellow), kinase module (blue). Subunits likely belonging to the Arm are shown by gray. Darker colors mark subunits, which are enriched in disordered regions.
Figure 5
Figure 5
Crystallographic analysis of Mediator Head module. (A) Crystal structure of the Head subunits from Saccharomyces cerevisiae by Imasaki et al. at 4.3 Å resolution and (B) crystal structure from Schizosaccharomyces pombe by Lariviere et al. at 3.9 Å resolution. Med6 (brown), Med17 (red), Med11 (wheat), Med8 (yellow), Med18 (lime), Med20 (blue), Med22 (orange). Gaps in the structure indicate disordered regions. Names of the different domains are indicated as underscored. (C) Topological arrangements of disordered regions in the Head module: fuzzy regions, which are disordered even in the complex, are yellow; disordered regions, which fold upon interaction, are orange; and ordered protein interaction sites are blue. The ID binding site in human Med17, where L371P mutation contributes to infantile cerebral atrophy, is shown by red.
Figure 6
Figure 6
Role of disorder in the Mediator formation. α-Helical molecular recognition element (red) mediates binding of Med8 to Med18 (dark gray)/Med20 (light gray) heterodimer. It is embedded in a larger disordered region.
Figure 7
Figure 7
ATP-dependent proteases share a common architecture. (A) Structure of the proteasome, as modeled from cryo-electron microscopy (PDB ID 4C0V; ATPγS bound). Two α, two β, and two Rpt subunits were removed to allow visualization of the interior. Only one-half (one α, one β ring) of the 20S core protease particle and one 19S regulatory particle are shown. (B) Structures of ClpX (PDB ID 3HWS; nucleotide-free) and ClpP (PDB ID 1Y6G), showing the interior of the barrel. Four out of six subunits of ClpX and four out of seven subunits of ClpP per ring are shown. (C) Structure of HslUV (PDB ID 1G3I; ATP-bound), showing the interior of the barrel. Four out of six subunits of HslU and V per ring are shown.
Figure 8
Figure 8
Adaptor proteins mediate degradation of some substrates. (A) The adaptor protein SspB (green) binds to ClpX (brown) through long flexible tails and to a substrate (blue) through the ssrA degradation tag (red), allowing it to present the substrate to ClpX. (B) The adaptor protein Rad23 contains a UbL domain (purple) that binds to receptors on the proteasome such as Rpn13, as well as two UBA domains (green) that can bind to ubiquitinated substrates (blue) and present them to the proteasome for degradation. The flexible linkers connecting Rad23 domains may help position substrates of different geometry such that their unstructured initiation regions (red) can engage with the proteasomal motors.
Figure 9
Figure 9
Initiation of degradation by the proteasome requires a disordered region. A substrate molecule (dihydrofolate reductase, PDB ID 1DRE; yellow and red cartoon on the left) with a polyubiquitin chain attached (in this case, linear tetra-ubiquitin, from PDB ID 2W9N, purple and cyan cartoon on the left) and a disordered region (red tail) can be degraded by the proteasome. First the polyubiquitin modification docks at the proteasome (PDB ID 4C0V), presumably to ubiquitin receptors Rpn10 (red) and Rpn13 (purple), either simultaneously (as shown) or individually. Next, the tail is engaged by the Rpt ATPase motors (orange) in an ATP-dependent process, allowing unfolding, translocation, and degradation (along with deubiquitination of the substrate) to begin.
Figure 10
Figure 10
Geometries of disordered initiation sites. A protein (blue) tagged with ubiquitin (purple) and containing a disordered initiation site (red) of sufficient length can be degraded by the proteasome. Initiation regions can be N-terminal (A), C-terminal (B), internal (C), or even on a nonubiquitinated protein in complex with a ubiquitinated protein (D; only blue protein is degraded). The site of ubiquitin modification may be on or near the disordered region.
Figure 11
Figure 11
Role of low complexity sequences in promoting the release of a fragment from the proteasome. (A) A protein targeted to the proteasome from the C-terminus will have the C-terminal portion of the protein degraded (green domain), but the presence of a low complexity region and an additional tightly folded domain (blue domain) leads to the release of a fragment consisting of the domain and a tail composed of part or all of the low complexity region. Only the endpoint of degradation is shown. (B) With a normal, high complexity sequence adjacent to the blue domain, a degradation intermediate will form composed of the blue domain bound to the proteasome. This intermediate will then partition between release and degradation, with degradation typically being faster (thicker arrow) leading to overall degradation of the fragment. (C) With a low complexity sequence adjacent to the blue domain, unfolding and degradation is slowed with little or no effect on release, leading to an overall reduction in degradation and accumulation of stable fragment, the same endpoint as shown in plot (A).
Figure 12
Figure 12
Mechanism of nucleocytoplasmic transport through NPCs. Importins (Kapβ1) identify and shuttle NLS-cargo from the cytoplasm into the nucleus. The Kapβ1–cargo complex is disassembled in the nucleus by RanGTP, and is thought to return to the cytosol with Kapβ1. NES-cargo requires both RanGTP and exportin for export through NPCs. RanGAP triggers the hydrolysis of RanGTP to RanGDP in the cytosol, which releases Kaps and cargoes. RanGDP is imported into the nucleus by NTF2, where it is recharged into RanGTP by RanGEF. In the absence of Kaps, neither specific nor large nonspecific cargoes can access the NPC.
Figure 13
Figure 13
Intrinsically disordered FG Nups fill the NPC. Estimated abundances (numbered) and FG Nup positions in S. cerevisiae. Each FG Nup is tethered on one terminal end to the inner walls of the NPC by an anchor domain from which the remaining FG-rich domain emanates to occupy the aqueous space within the central channel. Some FG Nups are symmetric (green), while others are exclusively cytoplasmic (red) or nuclear (blue). For clarity, each FG Nup varies in length, sequence, and number/type of FG-repeats (superscript). Error bars denote uncertainty with respect to their exact anchoring sites.
Figure 14
Figure 14
FG-centric NPC models. In this paradigm, the barrier mechanism is composed solely of FG Nups. Selective access is exclusive to Kaps (green) that bind the FG-repeats via multivalent interactions. Large nonspecific molecules (large red) are withheld due to insufficient binding with the FG-repeats. Small molecules (small red watermarked) diffuse freely through the barrier.
Figure 15
Figure 15
Kap-centric NPC model. Because of strong binding avidity, large numbers of Kap molecules are accommodated with the FG Nups. Slow Kaps that reside within the FG Nups (dark green) form integral barrier constituents. Weakly bound Kaps (light green) dominate fast transport due to limited penetration into the preoccupied FG Nups. Large nonspecific molecules (large red) are excluded from the pore. Small molecules (small red watermarked) diffuse freely through the barrier.
Figure 16
Figure 16
The FG Nups exhibit a rich material complexity. In vitro FG Nup behavior is sensitive to experimental design and length scale. Depending on the context, the FG Nups can exhibit different morphologies and materials properties, which can assemble into higher order structures. For instance, macroscopic hydrogels consist of several porous channels enmeshed within a scaffold provided by amyloid filaments. Each porous channel may be lined with FG Nups that bestows the hydrogel NPC-like functionality, as is the case for FG Nups tethered to artificial nanopores. See text for details.
Figure 17
Figure 17
Structural dissection of the X. laevis nucleosome core particle (PDB ID: 1AOI). (A) Complete nucleosome core particle wrapped in DNA (double white-pink ribbon). (B) The nucleosome core particle after the DNA removal. (C1 and C2) H2A–H2B dimers. (C1a) and (C1b) represent histones H2A (gray) and H2B (orange) of the first H2A–H2B dimer, whereas (C2a) and (C2b) show histones H2A (silver) and H2B (green) of the second H2A–H2B dimer. (D) (H3–H4)2 tetramer. (D1 and D2) H3–H4 dimers. (D1a) and (D1b) represent histones H3 (blue) and H4 (red) of the first H3–H4 dimer, whereas (D2a) and (D2b) show histones H3 (yellow) and H4 (tan) of the second H3–H4 dimer. All of these structures were visualized using the VMD software.
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