Guiding tail-anchored membrane proteins to the endoplasmic reticulum in a chaperone cascade

Shan, Shu‐ou

doi:10.1074/jbc.rev119.006197

Cited by 25 publications

(20 citation statements)

References 96 publications

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“…TA proteins are characterized by a single TMD at their C-terminus, which only becomes accessible to the cytoplasm after translation termination, necessitating post-translational recognition and targeting pathways for their membrane integration (Borgese et al, 2019). The most extensively studied pathway for targeting and insertion of endoplasmic reticulum (ER)destined TA proteins is the yeast guided entry of tail-anchored proteins (GET) pathway (transmembrane recognition complex [TRC] pathway in mammals; Mateja and Keenan, 2018;Shan, 2019). More recently, it was found that this widely conserved pathway works in parallel with the SRP-independent (SND) and ER membrane protein complex (EMC) pathways to mediate TA protein biogenesis at the ER (Aviram et al, 2016;Guna et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

et al. 2020

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Membrane protein biogenesis faces the challenge of chaperoning hydrophobic transmembrane helices for faithful membrane insertion. The guided entry of tail-anchored proteins (GET) pathway targets and inserts tail-anchored (TA) proteins into the endoplasmic reticulum (ER) membrane with an insertase (yeast Get1/ Get2 or mammalian WRB/CAML) that captures the TA from a cytoplasmic chaperone (Get3 or TRC40, respectively). Here, we present cryo-electron microscopy reconstructions, native mass spectrometry, and structure-based mutagenesis of human WRB/CAML/TRC40 and yeast Get1/Get2/Get3 complexes. Get3 binding to the membrane insertase supports heterotetramer formation, and phosphatidylinositol binding at the heterotetramer interface stabilizes the insertase for efficient TA insertion in vivo. We identify a Get2/ CAML cytoplasmic helix that forms a ''gating'' interaction with Get3/TRC40 important for TA insertion. Structural homology with YidC and the ER membrane protein complex (EMC) implicates an evolutionarily conserved insertion mechanism for divergent substrates utilizing a hydrophilic groove. Thus, we provide a detailed structural and mechanistic framework to understand TA membrane insertion.

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Section: Introductionmentioning

confidence: 99%

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

et al. 2020

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“…Despite some compensating mechanisms (see Section 4.1 ), TA proteins and short secretory proteins are released from the ribosome shortly after their synthesis is terminated without prior exposition of the targeting signal to the cytosol [ 151 ]. In such cases, a cascade of trans-acting factors handles the recognition, shielding, and delivery of the cargo [ 152 , 153 ]. Directionality of targeting towards the ER membrane is ensured by the homodimeric ATPase GET3 (Get3 in yeast), the central energy-consuming targeting factor of the GET pathway.…”

Section: Multifactorial Polypeptide Targeting Pathways: the Srp Get And Snd Systemsmentioning

confidence: 99%

“…How this model applies to the mammalian GET pathway remains to be clarified, since whether SGTA and BAG6 directly bind the ribosome with putative implications for initial cargo binding has been discussed (see Section 4.3 ). Nevertheless, the Hsp70-Sgt2-Get3 triad provides an attractive model for how directionality is maintained in the chaperone cascade [ 152 ]). Hsp70 is highly abundant in the cytosol and binds rapidly but loosely to its cargo which subsequently engages stronger interactions with chaperones downstream in the pathway.…”

Section: Multifactorial Polypeptide Targeting Pathways: the Srp Get And Snd Systemsmentioning

confidence: 99%

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum

Tirincsi

Sicking

Hadzibeganovic

et al. 2021

IJMS

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Looking at the variety of the thousands of different polypeptides that have been focused on in the research on the endoplasmic reticulum from the last five decades taught us one humble lesson: no one size fits all. Cells use an impressive array of components to enable the safe transport of protein cargo from the cytosolic ribosomes to the endoplasmic reticulum. Safety during the transit is warranted by the interplay of cytosolic chaperones, membrane receptors, and protein translocases that together form functional networks and serve as protein targeting and translocation routes. While two targeting routes to the endoplasmic reticulum, SRP (signal recognition particle) and GET (guided entry of tail-anchored proteins), prefer targeting determinants at the N- and C-terminus of the cargo polypeptide, respectively, the recently discovered SND (SRP-independent) route seems to preferentially cater for cargos with non-generic targeting signals that are less hydrophobic or more distant from the termini. With an emphasis on targeting routes and protein translocases, we will discuss those functional networks that drive efficient protein topogenesis and shed light on their redundant and dynamic nature in health and disease.

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“…On the other hand, within the GET pathway, tail-anchored membrane proteins (TA-MBPs) are transported to the ER membrane via a step-wise substrate transfer from highly promiscuous Hsp70 (Ssa1 in yeast) to the selective Get3 that traps TA-MBPs for membrane insertion. Such a cascade, engaging more specialized chaperones with increasing affinity allows for efficient, selective, and unidirectional targeting of nascent TAs, while protecting them from reaction with other cytoplasmic chaperones [reviewed in Shan (2019) ]. In a similar way, a network of chaperones including different Hsp40s, Sti, Hsp70 and Hsp90 is important for safeguarding mitochondrial precursor proteins across the cytoplasm Bykov et al (2020) .…”

Section: Conclusion: Emerging Patterns Of Client-chaperone Interactionsmentioning

confidence: 99%

How do Chaperones Bind (Partly) Unfolded Client Proteins?

Sučec

Bersch

Schanda

2021

Front. Mol. Biosci.

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Molecular chaperones are central to cellular protein homeostasis. Dynamic disorder is a key feature of the complexes of molecular chaperones and their client proteins, and it facilitates the client release towards a folded state or the handover to downstream components. The dynamic nature also implies that a given chaperone can interact with many different client proteins, based on physico-chemical sequence properties rather than on structural complementarity of their (folded) 3D structure. Yet, the balance between this promiscuity and some degree of client specificity is poorly understood. Here, we review recent atomic-level descriptions of chaperones with client proteins, including chaperones in complex with intrinsically disordered proteins, with membrane-protein precursors, or partially folded client proteins. We focus hereby on chaperone-client interactions that are independent of ATP. The picture emerging from these studies highlights the importance of dynamics in these complexes, whereby several interaction types, not only hydrophobic ones, contribute to the complex formation. We discuss these features of chaperone-client complexes and possible factors that may contribute to this balance of promiscuity and specificity.

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Guiding tail-anchored membrane proteins to the endoplasmic reticulum in a chaperone cascade

Cited by 25 publications

References 96 publications

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum

How do Chaperones Bind (Partly) Unfolded Client Proteins?

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