| Structural highlights
4pwx is a 6 chain structure with sequence from Baker's yeast. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Gene: | ARR4, D2371, GET3, Get3 YDL100C, YDL100C (Baker's yeast), GET4, GET4 YOR164C, O3580, YOR164C (Baker's yeast), GET5, GET5 MDY2 YOL111C, MDY2, TMA24, YOL111C (Baker's yeast) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[GET3_YEAST] ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum. Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors GET1 and GET2, where the tail-anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dimer state, facilitating recognition of newly synthesized TA membrane proteins. ATP hydrolysis is required for insertion. Subsequently, the homodimer reverts towards the open dimer state, lowering its affinity for the GET1-GET2 receptor, and returning it to the cytosol to initiate a new round of targeting. Cooperates with the HDEL receptor ERD2 to mediate the ATP-dependent retrieval of resident ER proteins that contain a C-terminal H-D-E-L retention signal from the Golgi to the ER. Involved in low-level resistance to the oxyanions arsenite and arsenate, and in heat tolerance.[1] [2] [3] [4] [5] [MDY2_YEAST] Required for efficient mating. Involved in the production of alpha-factor, the KAR9 and TUB1 location to the shmoo tip and nuclear migration into pheromone-induced shmoos.[6] [7] [GET4_YEAST] May play a role in insertion of tail-anchored proteins into the endoplasmic reticulum membrane.[8]
Publication Abstract from PubMed
Correct localization of membrane proteins is essential to all cells. Chaperone cascades coordinate the capture and handover of substrate proteins from the ribosomes to the target membranes, yet the mechanistic and structural details of these processes remain unclear. Here we investigate the conserved GET pathway, in which the Get4-Get5 complex mediates the handover of tail-anchor (TA) substrates from the cochaperone Sgt2 to the Get3 ATPase, the central targeting factor. We present a crystal structure of a yeast Get3-Get4-Get5 complex in an ATP-bound state and show how Get4 primes Get3 by promoting the optimal configuration for substrate capture. Structure-guided biochemical analyses demonstrate that Get4-mediated regulation of ATP hydrolysis by Get3 is essential to efficient TA-protein targeting. Analogous regulation of other chaperones or targeting factors could provide a general mechanism for ensuring effective substrate capture during protein biogenesis.
Crystal structure of ATP-bound Get3-Get4-Get5 complex reveals regulation of Get3 by Get4.,Gristick HB, Rao M, Chartron JW, Rome ME, Shan SO, Clemons WM Jr Nat Struct Mol Biol. 2014 May;21(5):437-42. doi: 10.1038/nsmb.2813. Epub 2014 Apr, 13. PMID:24727835[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shen J, Hsu CM, Kang BK, Rosen BP, Bhattacharjee H. The Saccharomyces cerevisiae Arr4p is involved in metal and heat tolerance. Biometals. 2003 Sep;16(3):369-78. PMID:12680698
- ↑ Schuldiner M, Collins SR, Thompson NJ, Denic V, Bhamidipati A, Punna T, Ihmels J, Andrews B, Boone C, Greenblatt JF, Weissman JS, Krogan NJ. Exploration of the function and organization of the yeast early secretory pathway through an epistatic miniarray profile. Cell. 2005 Nov 4;123(3):507-19. PMID:16269340 doi:S0092-8674(05)00868-8
- ↑ Schuldiner M, Metz J, Schmid V, Denic V, Rakwalska M, Schmitt HD, Schwappach B, Weissman JS. The GET complex mediates insertion of tail-anchored proteins into the ER membrane. Cell. 2008 Aug 22;134(4):634-45. PMID:18724936 doi:S0092-8674(08)00777-0
- ↑ Mariappan M, Mateja A, Dobosz M, Bove E, Hegde RS, Keenan RJ. The mechanism of membrane-associated steps in tail-anchored protein insertion. Nature. 2011 Aug 24;477(7362):61-6. doi: 10.1038/nature10362. PMID:21866104 doi:10.1038/nature10362
- ↑ Stefer S, Reitz S, Wang F, Wild K, Pang YY, Schwarz D, Bomke J, Hein C, Lohr F, Bernhard F, Denic V, Dotsch V, Sinning I. Structural Basis for Tail-Anchored Membrane Protein Biogenesis by the Get3-Receptor Complex. Science. 2011 Jun 30. PMID:21719644 doi:10.1126/science.1207125
- ↑ Iwanejko L, Smith KN, Loeillet S, Nicolas A, Fabre F. Disruption and functional analysis of six ORFs on chromosome XV: YOL117w, YOL115w ( TRF4), YOL114c, YOL112w ( MSB4), YOL111c and YOL072w. Yeast. 1999 Oct;15(14):1529-39. PMID:10514570 doi:<1529::AID-YEA457>3.0.CO;2-Y 10.1002/(SICI)1097-0061(199910)15:14<1529::AID-YEA457>3.0.CO;2-Y
- ↑ Hu Z, Potthoff B, Hollenberg CP, Ramezani-Rad M. Mdy2, a ubiquitin-like (UBL)-domain protein, is required for efficient mating in Saccharomyces cerevisiae. J Cell Sci. 2006 Jan 15;119(Pt 2):326-38. Epub 2006 Jan 3. PMID:16390866 doi:jcs.02754
- ↑ Jonikas MC, Collins SR, Denic V, Oh E, Quan EM, Schmid V, Weibezahn J, Schwappach B, Walter P, Weissman JS, Schuldiner M. Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum. Science. 2009 Mar 27;323(5922):1693-7. doi: 10.1126/science.1167983. PMID:19325107 doi:http://dx.doi.org/10.1126/science.1167983
- ↑ Gristick HB, Rao M, Chartron JW, Rome ME, Shan SO, Clemons WM Jr. Crystal structure of ATP-bound Get3-Get4-Get5 complex reveals regulation of Get3 by Get4. Nat Struct Mol Biol. 2014 May;21(5):437-42. doi: 10.1038/nsmb.2813. Epub 2014 Apr, 13. PMID:24727835 doi:http://dx.doi.org/10.1038/nsmb.2813
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