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Review
. 2017 May 24;4(5):483-494.
doi: 10.1016/j.cels.2017.04.006.

Systems-wide Studies Uncover Commander, a Multiprotein Complex Essential to Human Development

Anna L Mallam  1 , Edward M Marcotte  2
Affiliations
Review

Systems-wide Studies Uncover Commander, a Multiprotein Complex Essential to Human Development

Anna L Mallam et al. Cell Syst. .

Abstract

Recent mass spectrometry maps of the human interactome independently support the existence of a large multiprotein complex, dubbed "Commander." Broadly conserved across animals and ubiquitously expressed in nearly every human cell type examined thus far, Commander likely plays a fundamental cellular function, akin to other ubiquitous machines involved in expression, proteostasis, and trafficking. Experiments on individual subunits support roles in endosomal protein sorting, including the trafficking of Notch proteins, copper transporters, and lipoprotein receptors. Commander is critical for vertebrate embryogenesis, and defects in the complex and its interaction partners disrupt craniofacial, brain, and heart development. Here, we review the synergy between large-scale proteomic efforts and focused studies in the discovery of Commander, describe its composition, structure, and function, and discuss how it illustrates the power of systems biology. Based on 3D modeling and biochemical data, we draw strong parallels between Commander and the retromer cargo-recognition complex, laying a foundation for future research into Commander's role in human developmental disorders.

Keywords: Commander complex; developmental disorders; endosomal protein sorting; mammalian interactome; multiprotein complex; system-wide studies.

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Figures

Figure 1
Figure 1
Overview of the Commander complex. Commander is thought to contain up to 14 subunits equaling approximately 600 kDa in mass (Wan et al., 2015, Drew et al., 2017), is highly conserved in vertebrates, and functions in endosomal protein trafficking (Bartuzi et al., 2016; Li et al., 2015; Phillips-Krawczak et al., 2015). It also plays a crucial role in embryogenesis (Wan et al., 2015), and is linked to developmental disorders (Kolanczyk et al., 2015; Ritscher et al., 1987; Starokadomskyy et al., 2013). We suggest that Commander may function as a retromer-like sorter of cargo proteins within the endosomal system.
Figure 2
Figure 2
Putative Commander subunits. Recent human interaction networks describe overlapping pieces of the Commander complex. Three are experimentally derived and include a metazoan complex map (Wan et al., 2015, Drew et al., 2017), the ‘Bioplex’ network (Huttlin et al., 2015) and an interactome in ‘quantitative dimensions’ (Hein et al., 2015). Two are computational networks calculated using phylogenetic profiling (Dey et al., 2015) or ‘clustering by inferred models of evolution’ (CLIME) (Li et al., 2014). The 14 protein subunits identified by at least three studies are considered in this proposal as the strongest candidates to be core components of Commander (thick black line).
Figure 3
Figure 3
Evidence for Commander from small-scale proteomic studies. (A)-(F) Examples of published bait (red) and prey (orange) experiments with Commander subunits. (A) COMMD1 interacts with itself and all other COMMD proteins (Burstein et al., 2005). (B) CCDC22 binds COMMD1-10 (Starokadomskyy et al., 2013). (C) CCDC93 interacts with COMMD1-10 (Phillips-Krawczak et al., 2015). (D) A CCC complex of COMMD1-CCDC22-CCDC93 bound to C16orf62 has been extensively biochemically characterized, and is involved in endosomal protein trafficking (Bartuzi et al., 2016; Li et al., 2015; Phillips-Krawczak et al., 2015). (E) Other combinations of COMMDs have been seen to preferentially interact, for example COMMD3, -4 and -6 were identified in an early COMMD1 tandem affinity purification (TAP) screen (Burstein et al., 2005; Starokadomskyy et al., 2013). (F) We have verified several of the novel protein-protein interactions in the Commander complex by AP-MS (Wan et al., 2015). (G) Size exclusion chromatography of Commander measured by MS (Kirkwood et al., 2013). Elution profiles of all 14 putative Commander subunits indicate that they co-elute as a single entity of approximately 600 kDa in mass.
Figure 4
Figure 4
Commander is evolutionarily conserved and broadly expressed across human tissues. (A) Phylogenetic profiles for the presence and absence of each of the Commander genes were calculated for each of 66 species’ proteomes (Altenhoff et al., 2016). Dark grey = present; light grey = absent. (B) RNA and protein expression profiles for Commander genes in human cells. Tissue types are shown for which transcripts (source: FANTOM5 project) and protein (source: PaxDB) data are readily available. For RNA expression profiles, abundant = 2–150 and low = < 2 FPKM. For protein expression, abundant = 2–250 ppm and low = < 2 ppm. FPKM = Fragments Per Kilobase of transcript per Million mapped reads. (C) Subcellular localization of predicted Commander proteins as reported in Refs (Lindskog, 2015) (a), (Mao et al., 2011) (b), (Burkhead et al., 2009) (c), (Phillips-Krawczak et al., 2015) (d), (Drevillon et al., 2011) (e), (Chang et al., 2011) (f), (Li et al., 2015) (g), (de Bie et al., 2006) (h), and (Hu et al., 2006) (i).
Figure 5
Figure 5
Structural modeling and functional studies suggest roles for Commander. (A) Models for WASH-dependent endosomal protein trafficking by retromer (top) (based on Seaman et al., 2013) and Commander (bottom). (B) & (C) Structural data for the retromer cargo recognition complex. (B) Negative stain electron microscopy images of the human retromer cargo recognition complex (VPS26-VPS29-VPS35) of five representative structural classes. Images are reproduced from Hierro et al., 2007. (C) Small angle X-ray scattering (SAXS) model of the retromer VPS26 (purple)-VPS29 (green)-VPS35 (pink) complex, reproduced from Lucas at al., 2016. (D) Structural comparison of the retromer cargo recognition complex and core Commander subunits. Top: A structural model of a partial retromer cargo recognition complex (VPS26, red; SNX3, orange; and VPS35, purple) based on crystal structures (2R17 and 5F0J), electron microscopy, and SAXS (Hierro et al., 2007; Lucas at al., 2016). Bottom: A proposed structural model for core components of the Commander complex (DSCR3, red; COMMD1, orange; and C16orf62, purple) based on their similarities to retromer subunits. For homologous domains, the probability score calculated by HHPred (Soding, 2005) is shown. This represents the likelihood that they are true homologs when using Pfam as a database of template hidden Markov models (HMMs) (Finn et al., 2014). A score of greater than 95 % indicates that the homology is nearly certain. Crystal structures are available for the N- and C-terminus of human VPS35 (VPS35-N, residues 9-462, PDB = 5F0J; VPS35-C, residues 483-780, PDB = 2R17) and human VPS26 (PDB = 2FAU). These were used as templates to generate models of C16orf62 (C16orf62-N, residues 182-620); C16orf62-C, residues 629-926) and DSCR3, respectively, using MODELER (Sali and Blundell, 1993). Based on the predicted presence of a phosphoinositide-binding domain in the COMMDs, we suggest they occupy a homologous binding pocket to SNX3. (D) A structural comparison of the N-terminal domains of IFT81 (residues 1-109; PDB = 4LVP) and human NDC80 (residues 11-114; PDB = 2IGP) to the N-terminal domains of Commander CCDC22 (residues 1-109) and CCDC93 (residues 12-119), respectively. Homology scores were calculated by HHPred, and template structures were used to calculate models of CCDC22 and CCDC93 as described in (C). It is possible that the CH-domains in CCDC22 and CCDC93 function in microtubule binding. Interestingly, the C-terminal domains of both CCDC22 and CCDC93 show strong homology to tropomyosin (99 % and 95 %, respectively; PDB = 1C1G). (E) Phenotypic traits of defective Commander. Morpholino knockdown of COMMD2 or COMMD3 in X. laevis embryos causes defective head and eye development (left), and COMMD2/3 knockdown animals show altered neural patterning (right), including a posterior shift or loss of expression of mid-brain marker EN2 and of KROX20 (EGR1), the latter specifically in rhombomeres R3/R5. Images reproduced from Wan et al., 2015.
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