Publication Date:
2009-08-14
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mateja, Agnieszka -- Szlachcic, Anna -- Downing, Maureen E -- Dobosz, Malgorzata -- Mariappan, Malaiyalam -- Hegde, Ramanujan S -- Keenan, Robert J -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2009 Sep 17;461(7262):361-6. doi: 10.1038/nature08319. Epub 2009 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry & Molecular Biology, The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19675567" target="_blank"〉PubMed〈/a〉
Keywords:
Adenosine Diphosphate/metabolism
;
Adenosine Triphosphatases/*chemistry/*metabolism
;
Adenosine Triphosphate/metabolism
;
Aluminum Compounds/chemistry/metabolism
;
Crystallography, X-Ray
;
Fluorides/chemistry/metabolism
;
Guanine Nucleotide Exchange Factors/*chemistry/*metabolism
;
Hydrophobic and Hydrophilic Interactions
;
Membrane Proteins/chemistry/*metabolism
;
Methanococcus
;
Models, Molecular
;
Protein Binding
;
Protein Conformation
;
Protein Multimerization
;
Saccharomyces cerevisiae/*chemistry
;
Saccharomyces cerevisiae Proteins/*chemistry/*metabolism
;
Structure-Activity Relationship
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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