The structural basis of tail-anchored membrane protein recognition by Get3

Agnieszka Mateja, Anna Szlachcic, Maureen E. Downing, Malgorzata Dobosz, Malaiyalam Mariappan, Ramanujan S. Hegde and Robert J. Keenan ()
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Agnieszka Mateja: The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA
Anna Szlachcic: The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA
Maureen E. Downing: The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA
Malgorzata Dobosz: The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA
Malaiyalam Mariappan: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Room 101, Building 18T, 18 Library Drive, Bethesda, Maryland 20892, USA
Ramanujan S. Hegde: Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Room 101, Building 18T, 18 Library Drive, Bethesda, Maryland 20892, USA
Robert J. Keenan: The University of Chicago, Gordon Center for Integrative Science, Room W238, 929 East 57th Street, Chicago, Illinois 60637, USA

Nature, 2009, vol. 461, issue 7262, 361-366

Abstract: 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·AlF4--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.

Date: 2009
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DOI: 10.1038/nature08319

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