| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Targeting of newly synthesized membrane proteins to the endoplasmic reticulum is an essential cellular process. Most membrane proteins are recognized and targeted co-translationally by the signal recognition particle. However, nearly 5% of membrane proteins are 'tail-anchored' by a single carboxy-terminal transmembrane domain that cannot access the co-translational pathway. Instead, tail-anchored proteins are targeted post-translationally by a conserved ATPase termed Get3. The mechanistic basis for tail-anchored protein recognition or targeting by Get3 is not known. Here we present crystal structures of yeast Get3 in 'open' (nucleotide-free) and 'closed' (ADP.AlF(4)(-)-bound) dimer states. In the closed state, the dimer interface of Get3 contains an enormous hydrophobic groove implicated by mutational analyses in tail-anchored protein binding. In the open state, Get3 undergoes a striking rearrangement that disrupts the groove and shields its hydrophobic surfaces. These data provide a molecular mechanism for nucleotide-regulated binding and release of tail-anchored proteins during their membrane targeting by Get3.
The structural basis of tail-anchored membrane protein recognition by Get3.,Mateja A, Szlachcic A, Downing ME, Dobosz M, Mariappan M, Hegde RS, Keenan RJ Nature. 2009 Sep 17;461(7262):361-6. Epub 2009 Aug 12. PMID:19675567[6]
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
- ↑ Mateja A, Szlachcic A, Downing ME, Dobosz M, Mariappan M, Hegde RS, Keenan RJ. The structural basis of tail-anchored membrane protein recognition by Get3. Nature. 2009 Sep 17;461(7262):361-6. Epub 2009 Aug 12. PMID:19675567 doi:10.1038/nature08319
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