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PMID:19675567

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Citation

Mateja, A, Szlachcic, A, Downing, ME, Dobosz, M, Mariappan, M, Hegde, RS and Keenan, RJ (2009) The structural basis of tail-anchored membrane protein recognition by Get3. Nature 461:361-6

Abstract

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.

Links

PubMed Online version:10.1038/nature08319

Keywords

Adenosine Diphosphate/metabolism; Adenosine Triphosphatases/chemistry; Adenosine Triphosphatases/metabolism; Adenosine Triphosphate/metabolism; Aluminum Compounds/chemistry; Aluminum Compounds/metabolism; Crystallography, X-Ray; Fluorides/chemistry; Fluorides/metabolism; Guanine Nucleotide Exchange Factors/chemistry; Guanine Nucleotide Exchange Factors/metabolism; Hydrophobic and Hydrophilic Interactions; Membrane Proteins/chemistry; Membrane Proteins/metabolism; Methanococcus; Models, Molecular; Protein Binding; Protein Conformation; Protein Multimerization; SEC Translocation Channels; Saccharomyces cerevisiae/chemistry; Saccharomyces cerevisiae Proteins/chemistry; Saccharomyces cerevisiae Proteins/metabolism; Structure-Activity Relationship

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SC61B

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q12154

F

Seeded From UniProt

complete

YEAST:GET3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P60468

F

Seeded From UniProt

complete

SCHPO:GET3

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9P7F8

F

Seeded From UniProt

complete

YEAST:GET3

enables

GO:0042802: identical protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q12154

F

Seeded From UniProt

complete

Notes

See also

References

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