Structure and Interactions of the Endogenous Human Commander Complex

Laulumaa, Saara; Kumpula, Esa-Pekka; Huiskonen, J.T.; Varjosalo, Markku

doi:10.2139/ssrn.4399565

Cited by 4 publications

(6 citation statements)

References 51 publications

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“…Retriever is assembled around a central VPS35L subunit to which VPS26C and VPS29 associate at spatially distant amino-and carboxy-terminal regions of the VPS35L asolenoid (Fig. 1B) (Boesch et al, 2023;Healy et al, 2023;Laulumaa et al, 2023). We employed AlphaFold2 modelling (Jumper et al, 2021;Mirdita et al, 2022) to predict the association between Retriever and the unstructured human SNX17 tail corresponding to residues Gly400-to-Leu470.…”

Section: Snx17 Associates With Commander Via Its Extended C-terminal ...mentioning

confidence: 99%

“…Central to network function are multiprotein complexes that coordinate sequence-dependent recognition of integral proteins with the biogenesis of vesicular and tubular transport carriers (McNally and Cullen, 2018;Chen et al, 2019;McDonald, 2021). Retriever is an essential cargo sorting complex and is a stable heterotrimer of VPS26C, VPS35L and VPS29, that together with the dodecameric CCDC22, CCDC93, COMMD (CCC) complex and DENND10, forms the 16subunit Commander super-assembly (Phillips-Krawczak et al, 2015;Mallam and Marcotte, 2017;McNally et al, 2017;Boesch et al, 2023;Healy et al, 2023;Laulumaa et al, 2023). Defects in Commander assembly and function are associated with metabolic disorders including hypercholesterolemia (Bartuzi et al, 2016;Fedoseienko et al, 2018;Rimbert et al, 2020;Vos et al, 2023), viral infection (Daniloski et al, 2021;Zhu et al, 2021), and lead to Ritscher-Schinzel syndrome, a multi-system developmental disorder characterized by abnormal craniofacial features, cerebellar hypoplasia, and stunted cardiovascular development (Kolanczyk et al, 2015;Kato et al, 2020;Otsuji et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

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Mechanism and regulation of cargo entry into the Commander recycling pathway

Butkovič,

Walker,

Healy

et al. 2024

Preprint

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Commander is a multiprotein complex that orchestrates endosomal recycling of diverse integral cargo proteins and in humans is required for normal skeletal, brain, kidney, and cardiovascular development. While the structure of this complex has recently been described, the central question of how cargo proteins are selected for entry into the Commander recycling pathway remains unclear. Here using recombinant protein reconstitution andin silicopredictions we identify the evolutionary conserved mechanism through which the unstructured carboxy-terminal tail of the integral protein adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the carboxy tail for Retriever association. Using molecular cell biology and high-resolution microscopy, we establish the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains for entry into the recycling pathway. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting complex.

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Section: Snx17 Associates With Commander Via Its Extended C-terminal ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism and regulation of cargo entry into the Commander recycling pathway

Butkovič,

Walker,

Healy

et al. 2024

Preprint

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“…For the lysosomal degradative pathway, the cargoes are typically sorted by the Endosomal Sorting Complex Required for Transport (ESCRT) machinery, while recycling of cargoes to either the plasma membrane or the trans-Golgi network (TGN) is primarily driven by tubulovesicular carriers. The evolutionarily conserved Retromer complex is one of the key protein machineries controlling the cargo recycling and sorting at the endosome and is conserved from humans to the simplest singlecelled eukaryotes [1][2][3][4][5][6][7] . Mutations in or altered expression of Retromer disrupt cellular homeostasis and have been strongly linked to a number of human diseases including Alzheimer's [8][9][10][11] , Parkinson's disease [12][13][14][15] and more recently carcinogenesis 16 .…”

Section: Introductionmentioning

confidence: 99%

“…Retromer-binding capacity but have instead evolved sequences in their N-terminal domains for binding distinct but functionally related proteins such as SNX2753,54 . Furthermore, the site in VPS29 that binds to PL-containing motifs has itself been adapted in the human protein to mediate interactions with human specific proteins including the Rab7 GAP TBC1D535 and VPS35-related protein VPS35L[5][6][7] . How such activities have evolved, and how they are regulated across species will be an important question for the future.…”

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confidence: 99%

Molecular basis for the assembly of the Vps5-Vps17 SNX-BAR proteins with Retromer

Chen,

Tillu,

Gopaldass

et al. 2024

Preprint

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Retromer mediates endosomal retrieval of transmembrane proteins in all eukaryotes and was first discovered in yeast in complex with the Vps5 and Vps17 sorting nexins (SNXs). Cryoelectron tomography (cryoET) studies of Retromer-Vps5 revealed a pseudo-helical coat on membrane tubules where dimers of the Vps26 subunit bind Vps5 membrane-proximal domains. However, the Vps29 subunit is also required for Vps5-Vps17 association despite being far from the membrane. Here, we show that Vps5 binds both Vps29 and Vps35 subunits through its unstructured N-terminal domain. A Pro-Leu (PL) motif in Vps5 binds Vps29 and is required for association with Retromer on membrane tubules in vitro, and for the proper recycling of the Vps10 cargo in Saccharomyces cerevisiae. CryoET of Retromer tubules with Vps5-Vps17 heterodimers show a similar architecture to the coat with Vps5-Vps5 homodimers, however, the spatial relationship between Retromer units is highly restricted, likely due to more limited orientations for docking. These results provide new mechanistic insights into how Retromer and SNX-BAR association has evolved across species.

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“…1a), Retriever is remotely related to the well-studied endosomal recycling complex Retromer 1–3 , which handles a separate subset of cargoes. Recent studies have revealed that while Retriever shares a similar overall architecture with Retromer, it possesses distinct structural features and regulatory mechanisms 4–7 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for Retriever-SNX17 assembly and endosomal sorting

Singla,

Boesch,

Joyce Fung

et al. 2024

Preprint

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During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we report the structure of the Retriever-SNX17 complex determined using cryogenic electron microscopy (cryo-EM). Our structure reveals that the C-terminal tail of SNX17 engages with a highly conserved interface between the VPS35L and VPS26C subunits of Retriever. Through comprehensive biochemical, cellular, and proteomic analyses, we demonstrate that disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargos and altering the composition of the plasma membrane proteome. Intriguingly, we find that the SNX17-binding pocket on Retriever can be utilized by other ligands that share a consensus acidic C-terminal tail motif. By showing how SNX17 is linked to Retriever, our findings uncover a fundamental mechanism underlying endosomal trafficking of critical cargo proteins and reveal a mechanism by which Retriever can engage with other regulatory factors.

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Structure and Interactions of the Endogenous Human Commander Complex

Cited by 4 publications

References 51 publications

Mechanism and regulation of cargo entry into the Commander recycling pathway

Mechanism and regulation of cargo entry into the Commander recycling pathway

Molecular basis for the assembly of the Vps5-Vps17 SNX-BAR proteins with Retromer

Structural basis for Retriever-SNX17 assembly and endosomal sorting

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