Get5 Carboxyl-terminal Domain Is a Novel Dimerization Motif That Tethers an Extended Get4/Get5 Complex

Chartron, J.W.; VanderVelde, David; Rao, Meera; Clemons, William M.

doi:10.1074/jbc.m111.333252

Cited by 28 publications

(39 citation statements)

References 53 publications

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“…Get4 is an alpha helical repeat protein that tightly binds to the N-terminal domain of Get5 [33-35]. The Get5 sequence is followed by a ubiquitin-like domain (Ubl) and a C-terminal homodimerization domain, resulting in an extended heterotetrameric complex [35,36] (Fig. 4F).…”

Section: Sgt2 Get4 and Get5 Load Get3 With Ta-proteinmentioning

confidence: 99%

The complex process of GETting tail-anchored membrane proteins to the ER

Chartron

Clemons

Suloway

2012

Current Opinion in Structural Biology

100

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Biosynthesis of membrane proteins requires that hydrophobic transmembrane (TM) regions be shielded from the cytoplasm while being directed to the correct membrane. Tail-anchored (TA) membrane proteins, characterized by a single C-terminal TM, pose an additional level of complexity because they must be post-translationally targeted. In eukaryotes, the GET pathway shuttles TA-proteins to the endoplasmic reticulum. The key proteins required in yeast (Sgt2 and Get1-5) have been under extensive structural and biochemical investigation during recent years. The central protein Get3 utilizes nucleotide linked conformational changes to facilitate substrate loading and targeting. Here we analyze this complex process from a structural perspective, as understood in yeast, and further postulate on similar pathways in other domains of life.

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Section: Sgt2 Get4 and Get5 Load Get3 With Ta-proteinmentioning

confidence: 99%

The complex process of GETting tail-anchored membrane proteins to the ER

Chartron

Clemons

Suloway

2012

Current Opinion in Structural Biology

100

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“…Sgt2’s N-terminal domain mediates both homodimerization and binding to the central, ubiquitin-like domain of Get5 (Chang et al, 2010; Chartron et al, 2011; Liou and Wang, 2005). The C-terminal domain of Get5 assumes a novel, helical bundle fold that mediates homodimerization (Chartron et al, 2012b). Get4 is an elongated, α-helical solenoid (Bozkurt et al, 2010; Chang et al, 2010; Chartron et al, 2010) that forms a tight complex with the N-terminus of Get5 at one end and a more labile complex with Get3 at the other (Chang et al, 2010; Chartron et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Targeting and Insertion of Tail-Anchored Membrane Proteins by the GET Pathway

Denic

Dötsch

Sinning

2013

Cold Spring Harbor Perspectives in Biology

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Hundreds of eukaryotic membrane proteins are anchored to membranes by a single transmembrane domain at their C-terminus. Many of these tail-anchored (TA) proteins are post-translationally targeted to the endoplasmic reticulum (ER) membrane for insertion by the Guided-Entry of TA protein insertion (GET) pathway. In recent years most of the components of this conserved pathway have been biochemically and structurally characterized. Get3 is the pathway targeting factor that utilizes nucleotide-linked conformational changes to mediate the delivery of TA proteins between the GET pre-targeting machinery in the cytosol and the transmembrane pathway components in the ER. Here we focus on the mechanism of the yeast GET pathway and make a speculative analogy between its membrane insertion step and the ATPase-driven cycle of ABC transporters.

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“…Although Bag6 is missing in fungi, the analogous yeast complex contains two proteins, Get4 and Get5/ Mdy2, which are homologs of the mammalian proteins TRC35 and Ubl4A, respectively. In yeast, these two proteins form a heterotetramer that regulates the handoff of the TA protein from the cochaperone small, glutamine-rich, tetratricopeptide repeat protein 2 (Sgt2) [small glutamine-rich tetratricopeptide repeat-containing protein (SGTA) in mammals] to the delivery factor Get3 (TRC40 in mammals) (19)(20)(21)(22). It is expected that the mammalian homologs, along with Bag6, play a similar role (23)(24)(25)(26)(27).…”

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confidence: 99%

“…3B). Although fungal Get5 forms a stable homodimer mediated by Get5-C, Ubl4A alone is primarily a monomer (20). Because Ubl4A forms a heterodimer with Bag6, one might expect a novel fold for Ubl4A-C; instead, the Ubl4A-C heterodimerization domain has a structure identical to the Get5-C homodimerization domain, an rmsd of 0.94 Å for equivalent backbone residues (Fig.…”

mentioning

confidence: 99%

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

Mock

Chartron

Zaslaver

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

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BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6–Ubl4A dimer demonstrates that Bag6–BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein α to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6.

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Get5 Carboxyl-terminal Domain Is a Novel Dimerization Motif That Tethers an Extended Get4/Get5 Complex

Cited by 28 publications

References 53 publications

The complex process of GETting tail-anchored membrane proteins to the ER

The complex process of GETting tail-anchored membrane proteins to the ER

Endoplasmic Reticulum Targeting and Insertion of Tail-Anchored Membrane Proteins by the GET Pathway

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

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