Structure and activation mechanism of the BBSome membrane protein trafficking complex

Singh, Sandeep; Gui, Miao; Koh, Fujiet; Yip, M.C.J.; Brown, Alan

doi:10.7554/elife.53322

Cited by 65 publications

(50 citation statements)

References 87 publications

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“…Our previous study has shown that RABL5/IFT22 binds and stabilizes BBS3 independent of their nucleotide states in the cell body ( Xue et al, 2020 ). Since the GTP-bound configuration is related to BBS3’s ability to associate with the membrane ( Jin et al, 2010 ; Klink et al, 2020 ; Liew et al, 2014 ; Mourão et al, 2014 ; Singh et al, 2020 ; Zhang et al, 2011 ), IFT22 binding to BBS3 in the cell body could prevent BBS3 from associating with the cell membrane. Before ciliary entry, IFT22 is released from BBS3 at the basal body, which will enable the GTP-bound BBS3 to be in a state to attach to the membrane for lateral transport into cilia ( Figure 8 ).…”

Section: Discussionmentioning

confidence: 99%

Bardet–Biedl syndrome 3 protein promotes ciliary exit of the signaling protein phospholipase D via the BBSome

Liu

Xue

Sun

et al. 2021

eLife

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Certain ciliary signaling proteins couple with the BBSome, a conserved complex of Bardet-Biedl syndrome (BBS) proteins, to load onto retrograde intraflagellar transport (IFT) trains for their removal out of cilia in Chlamydomonas reinhardtii. Here, we show that loss of the Arf-like 6 (ARL6) GTPase BBS3 causes the signaling protein phospholipase D (PLD) to accumulate in cilia. Upon targeting to the basal body, BBSomes enter and cycle through cilia via IFT, while BBS3 in a GTP-bound state separates from BBSomes, associates with the membrane, and translocates from the basal body to cilia by diffusion. Upon arriving at the ciliary tip, GTP-bound BBS3 binds and recruits BBSomes to the ciliary membrane for interacting with PLD, thus making the PLD-laden BBSomes available to load onto retrograde IFT trains for ciliary exit. Therefore, BBS3 promotes PLD exit from cilia via the BBSome providing a regulatory mechanism for ciliary signaling protein removal out of cilia.

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Section: Discussionmentioning

confidence: 99%

Bardet–Biedl syndrome 3 protein promotes ciliary exit of the signaling protein phospholipase D via the BBSome

Liu

Xue

Sun

et al. 2021

eLife

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“…In contrast, purified IFT172, an IFT-B component that is also homologous to COPI and ' like WDR35, can not only assemble on liposomes with high affinity but can also bud 50nm vesicles consistent with coatomer sized products (Wang et al, 2018). Together this evolutionary conservation of the BB-Some with coatomer proteins (Jékely and Arendt, 2006;van Dam et al, 2013), interaction with in vitro membranes in presence of ARF like GTPase ARL-6, interaction with phospholipids (Jin et al, 2010;Nachury et al, 2007) and recent cryoEM structures of the complex (Chou et al, 2019;Klink et al, 2020;Singh et al, 2020;Yang et al, 2020) suggest the BBSome may be working as an adaptor for IFT-A mediated cage formation, similar to other coat adaptors for clathrin (i.e.AP1/AP2) or COP (i.e. -, -, -, and -COP for COPI).…”

Section: Discussionmentioning

confidence: 90%

A WDR35-dependent coatomer transports ciliary membrane proteins from the Golgi to the cilia

Quidwai

Hall

Keighren

et al. 2020

Preprint

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Intraflagellar transport (IFT) is a highly conserved mechanism for motor-driven transport of cargo within cilia, but how this cargo is selectively transported to cilia and across the diffusion barrier is unclear. WDR35/IFT121 is a component of the IFT-A complex best known for its role in ciliary retrograde transport. In the absence of WDR35, small mutant cilia form but fail to enrich in diverse classes of ciliary membrane proteins. In Wdr35 mouse mutants, the IFT-A peripheral components are degraded and core components accumulate at the transition zone. We reveal deep sequence homology and structural similarity of WDR35 and other IFT-As to the coatomer COPI proteins α and β ′, and demonstrate an accumulation of coat-less vesicles which fail to fuse with Wdr35 mutant cilia. Our data provides the first in-situ evidence of a novel coatomer function for WDR35 likely with other IFT-A proteins in delivering ciliary membrane cargo from the Golgi necessary for cilia elongation.

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“…The BBSome, which shares homology with vesicle coats and adaptors, exists in a soluble autoinhibited state that is activated by the active form of a small GTPase, ARL6, leading to formation of planar membrane coats through interactions with both PIPs and transmembrane cargoes, like GPCRs [60,[79][80][81][82][83]. Recent structural work sheds light on BBSome membrane recruitment and GPCR interactions [79][80][81][82][83]. When active, the BBSome uses a positively charged surface to interact with the negative membrane, while IFT-binding sites on the BBSome face away from membrane.…”

Section: Role Of the Bbsome In Htr6 And Sstr3 Ciliary Targetingmentioning

confidence: 99%

HTR6 and SSTR3 targeting to primary cilia

Barbeito

Garcia-Gonzalo

2021

Biochemical Society Transactions

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Primary cilia are hair-like projections of the cell membrane supported by an inner microtubule scaffold, the axoneme, which polymerizes out of a membrane-docked centriole at the ciliary base. By working as specialized signaling compartments, primary cilia provide an optimal environment for many G protein-coupled receptors (GPCRs) and their effectors to efficiently transmit their signals to the rest of the cell. For this to occur, however, all necessary receptors and signal transducers must first accumulate at the ciliary membrane. Serotonin receptor 6 (HTR6) and Somatostatin receptor 3 (SSTR3) are two GPCRs whose signaling in brain neuronal cilia affects cognition and is implicated in psychiatric, neurodegenerative, and oncologic diseases. Over a decade ago, the third intracellular loops (IC3s) of HTR6 and SSTR3 were shown to contain ciliary localization sequences (CLSs) that, when grafted onto non-ciliary GPCRs, could drive their ciliary accumulation. Nevertheless, these CLSs were dispensable for ciliary targeting of HTR6 and SSTR3, suggesting the presence of additional CLSs, which we have recently identified in their C-terminal tails. Herein, we review the discovery and mapping of these CLSs, as well as the state of the art regarding how these CLSs may orchestrate ciliary accumulation of these GPCRs by controlling when and where they interact with the ciliary entry and exit machinery via adaptors such as TULP3, RABL2 and the BBSome.

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Structure and activation mechanism of the BBSome membrane protein trafficking complex

Cited by 65 publications

References 87 publications

Bardet–Biedl syndrome 3 protein promotes ciliary exit of the signaling protein phospholipase D via the BBSome

Bardet–Biedl syndrome 3 protein promotes ciliary exit of the signaling protein phospholipase D via the BBSome

A WDR35-dependent coatomer transports ciliary membrane proteins from the Golgi to the cilia

HTR6 and SSTR3 targeting to primary cilia

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