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. 2013;9(7):e1003144.
doi: 10.1371/journal.pcbi.1003144. Epub 2013 Jul 18.

Structural Disorder Provides Increased Adaptability for Vesicle Trafficking Pathways

Free PMC article

Structural Disorder Provides Increased Adaptability for Vesicle Trafficking Pathways

Natalia Pietrosemoli et al. PLoS Comput Biol. .
Free PMC article


Vesicle trafficking systems play essential roles in the communication between the organelles of eukaryotic cells and also between cells and their environment. Endocytosis and the late secretory route are mediated by clathrin-coated vesicles, while the COat Protein I and II (COPI and COPII) routes stand for the bidirectional traffic between the ER and the Golgi apparatus. Despite similar fundamental organizations, the molecular machinery, functions, and evolutionary characteristics of the three systems are very different. In this work, we compiled the basic functional protein groups of the three main routes for human and yeast and analyzed them from the structural disorder perspective. We found similar overall disorder content in yeast and human proteins, confirming the well-conserved nature of these systems. Most functional groups contain highly disordered proteins, supporting the general importance of structural disorder in these routes, although some of them seem to heavily rely on disorder, while others do not. Interestingly, the clathrin system is significantly more disordered (~23%) than the other two, COPI (~9%) and COPII (~8%). We show that this structural phenomenon enhances the inherent plasticity and increased evolutionary adaptability of the clathrin system, which distinguishes it from the other two routes. Since multi-functionality (moonlighting) is indicative of both plasticity and adaptability, we studied its prevalence in vesicle trafficking proteins and correlated it with structural disorder. Clathrin adaptors have the highest capability for moonlighting while also comprising the most highly disordered members. The ability to acquire tissue specific functions was also used to approach adaptability: clathrin route genes have the most tissue specific exons encoding for protein segments enriched in structural disorder and interaction sites. Overall, our results confirm the general importance of structural disorder in vesicle trafficking and suggest major roles for this structural property in shaping the differences of evolutionary adaptability in the three routes.

Conflict of interest statement

The authors have declared that no competing interests exist.


Figure 1
Figure 1. Disorder content for functional groups of proteins involved in vesicle trafficking.
Disorder content (%) predicted by the IUPred method for the main functional groups of vesicle trafficking proteins in human (A) and yeast (B). Data are shown in Table 1. The main functional groups are COAT (coat proteins), ASP (adaptors and sorting proteins), EARP (enzymatic activity related proteins), UCP (unclassified proteins), MSTC (multisubunit tethering complexes), OFRP (other fusion regulatory proteins), SNARE (SNARE proteins) and NTSR (neurotransmitter transport specific regulators). The bottom and top border of the boxes represent 25% and 75% of the data respectively, while the bold line in the middle stands for the median (50%). The whiskers stand for the minimum and maximum values in the dataset. The mean is depicted by a red star. Proteins with disorder content (30% ≤ d.c. < 50%) are considered fairly disordered, while proteins with more than 50% disorder content are highly disordered.
Figure 2
Figure 2. Interactions between the disordered N-terminal tails of SNARE proteins and their globular SM protein partners.
Three PDB structures are presented showing the interaction between distinct pairs of the syntaxin-family SNARE proteins and their regulatory SM-proteins, an interaction that has been shown to positively regulate the SNARE complex assembly. The N-terminal of the SNARE partner is predicted to be mostly disordered (more than 50% of its residues) in the unbound form in all cases. (A) Interaction between the yeast syntaxin-family SNARE Sed5 N-terminal region, and SM protein Sly1 (PDB: 1MQS). (B) Interaction between the N-terminal tail of syntaxin-4 and syntaxin-binding protein 3 from mouse (PDB: 2PJX). (C) Interaction between syntaxin-1A (structure lacking the C-terminal transmembrane region) and syntaxin-binding protein 1 from rat (PDB: 3C98). Each interaction pair is represented by a PDB structure (left) and a domain map of the entire protein chain for both partners (right). The upper domain map corresponds to the SNARE protein, while the bottom one to the SM partner. In the structures, the disordered SNARE N-terminal tails are represented with cartoon style (magenta) while the partner molecule is in surface representation (white). In panel C, the remaining part of syntaxin-1A, which is not part of the disordered N-terminal tail, is coloured purple-blue, and those disordered residues of the N-terminal missing from the X-ray structure (10–26) are represented by a dashed-line. Names and lengths are provided for each protein in the corresponding domain map. Names and locations of their known Pfam domains (predicted by the PfamScan method) are also indicated. Regions predicted to be disordered (length of at least 3 consecutive residues) by IUPred are coloured in magenta, while the ordered segments are white (if not predicted to be part of a Pfam domain) or light-gray (if they are). Regions present in the PDB structures are marked by stars.
Figure 3
Figure 3. Comparison of systems in budding-associated functional groups of proteins.
Comparison of disorder contents (%) predicted by the IUPred method between proteins involved in the three main vesicle trafficking systems for human (A) and yeast (B). Only data on budding and fission related proteins are presented here, since those could be reliably grouped according to the three main systems. Corresponding data are shown in Table 1. The bottom and top border of the boxes represent 25% and 75% of the data respectively, while the bold line in the middle stands for the median (50%). The whiskers stand for the minimum and the maximum of the data, while the mean is depicted by a small red star.
Figure 4
Figure 4. Interactions between pairs of clathrin-associated adaptor proteins.
Complexes formed between clathrin-associated adaptor proteins are presented, in which one partner interacts with a region predicted to be structurally disordered in the unbound form. On the first three panels, the α2 subunit of mouse Ap-2 is the folded partner interacting with (A) rat epsin-1 (PDB 1KY6), (B) mouse intersectin-1 (PDB 3HS8); and (C) mouse EPS15 (Epidermal growth factor receptor substrate 15, PDB: 1KYF). In panel D, a relatively long disordered segment of human stonin-2 interacts with one folded EF-hand domain of human EPS15 (PDB: 2JXC). In each panel, the structure of the complex is depicted on the left and a domain map for each partner is depicted on the right. The top domain map represents the partner that is binding through the structurally disordered region. In panels A to C, the disordered peptides are represented with sticks (purple) while the folded partner is shown in surface representation (white). In panel D, the long disordered segment of human stonin-2 is shown in cartoon representation. For each protein, the domain maps indicate the names and locations of the known Pfam domains (predicted by the PfamScan method), and are shown in gray segments. Regions predicted to be disordered by IUPred are marked in purple segments; regions present in the PDB structure are marked by stars.
Figure 5
Figure 5. Structural comparison of orthologous proteins involved in vesicle trafficking.
The structural characteristics of two orthologous protein pairs from the COPII vesicle trafficking system are presented. On panel A, the moderately disordered (34.13%) human Sec24A COPII adaptor subunit is compared to its virtually ordered (5.94%) yeast ortholog (SFB2, Sec24 related protein). On panel B, the highly disordered human Sec16A (71.41%) and yeast Sec16 (74.44%) proteins are presented. The disorder pattern predicted by the IUPred method is plotted for the members of each pair (blue curve), where the black dashed line (y = 0.5) represents the cut-off between order and disorder. Residues with disorder tendency above this cut-off are considered to be disordered. A domain map is also presented for each protein. In it, the location and names of their identified Pfam domains (gray segments) and their disordered binding regions predicted by the Anchor method (blue segments) are shown. In each panel, the human ortholog is depicted in the top part: the disorder prediction curve followed by its corresponding domain map. The bottom part of each panel is a specular representation of the corresponding yeast ortholog: the disorder curve is topped by the domain map. The corresponding disorder curves and domain maps are fitted in length so that structural information can be directly reflected on the disorder pattern. The blue dashed line connecting the domain maps in panel A shows the position in the human ortholog which corresponds to the N-terminal end of its yeast ortholog.

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    1. Beck R, Rawet M, Wieland FT, Cassel D (2009) The COPI system: molecular mechanisms and function. FEBS Lett 583: 2701–2709. - PubMed
    1. Bethune J, Wieland F, Moelleken J (2006) COPI-mediated transport. J Membr Biol 211: 65–79. - PubMed
    1. Hsu VW, Yang JS (2009) Mechanisms of COPI vesicle formation. FEBS Lett 583: 3758–3763. - PMC - PubMed
    1. Sato K, Nakano A (2007) Mechanisms of COPII vesicle formation and protein sorting. FEBS Lett 581: 2076–2082. - PubMed
    1. Stagg SM, LaPointe P, Balch WE (2007) Structural design of cage and coat scaffolds that direct membrane traffic. Curr Opin Struct Biol 17: 221–228. - PubMed

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This work was supported by the Research Foundation Flanders (FWO) Odysseus grant G.0029.12. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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