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Title: Msp1 Is a Membrane Protein Dislocase for Tail-Anchored Proteins

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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Cell; Journal Volume: 67; Journal Issue: 2
Country of Publication:
United States

Citation Formats

Wohlever, Matthew L., Mateja, Agnieszka, McGilvray, Philip T., Day, Kasey J., and Keenan, Robert J. Msp1 Is a Membrane Protein Dislocase for Tail-Anchored Proteins. United States: N. p., 2017. Web. doi:10.1016/j.molcel.2017.06.019.
Wohlever, Matthew L., Mateja, Agnieszka, McGilvray, Philip T., Day, Kasey J., & Keenan, Robert J. Msp1 Is a Membrane Protein Dislocase for Tail-Anchored Proteins. United States. doi:10.1016/j.molcel.2017.06.019.
Wohlever, Matthew L., Mateja, Agnieszka, McGilvray, Philip T., Day, Kasey J., and Keenan, Robert J. 2017. "Msp1 Is a Membrane Protein Dislocase for Tail-Anchored Proteins". United States. doi:10.1016/j.molcel.2017.06.019.
title = {Msp1 Is a Membrane Protein Dislocase for Tail-Anchored Proteins},
author = {Wohlever, Matthew L. and Mateja, Agnieszka and McGilvray, Philip T. and Day, Kasey J. and Keenan, Robert J.},
abstractNote = {},
doi = {10.1016/j.molcel.2017.06.019},
journal = {Molecular Cell},
number = 2,
volume = 67,
place = {United States},
year = 2017,
month = 7
  • 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 {center_dot} AlF{sub 4}{sup -}-bound) dimer states. In the closed state, the dimermore » 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.« less
  • Tail-anchored (TA) proteins represent a unique class of membrane proteins that contain a single C-terminal transmembrane helix. The post-translational insertion of the yeast TA proteins into the ER membrane requires the Golgi ER trafficking (GET) complex which contains Get1, Get2 and Get3. Get3 is an ATPase that recognizes and binds the C-terminal transmembrane domain (TMD) of the TA proteins. We have determined the crystal structures of Get3 from two yeast species, S. cerevisiae and D. hansenii, respectively. These high resolution crystal structures show that Get3 contains a nucleotide-binding domain and a 'finger' domain for binding the TA protein TMD. Amore » large hydrophobic groove on the finger domain of S. cerevisiae Get3 structure might represent the binding site for TMD of TA proteins. A hydrophobic helix from a symmetry-related Get3 molecule sits in the TMD-binding groove and mimics the TA binding scenario. Interestingly, the crystal structures of the Get3 dimers from S. cerevisiae and D. hansenii exhibit distinct conformations. The S. cerevisiae Get3 dimer structure does not contain nucleotides and maintains an 'open' conformation, while the D. hansenii Get3 dimer structure binds ADP and stays in a 'closed' conformation. We propose that the conformational changes to switch the Get3 between the open and closed conformations may facilitate the membrane insertions for TA proteins.« less
  • Tail-anchored (TA) membrane proteins destined for the endoplasmic reticulum are chaperoned by cytosolic targeting factors that deliver them to a membrane receptor for insertion. Although a basic framework for TA protein recognition is now emerging, the decisive targeting and membrane insertion steps are not understood. Here we reconstitute the TA protein insertion cycle with purified components, present crystal structures of key complexes between these components and perform mutational analyses based on the structures. We show that a committed targeting complex, formed by a TA protein bound to the chaperone ATPase Get3, is initially recruited to the membrane through an interactionmore » with Get2. Once the targeting complex has been recruited, Get1 interacts with Get3 to drive TA protein release in an ATPase-dependent reaction. After releasing its TA protein cargo, the now-vacant Get3 recycles back to the cytosol concomitant with ATP binding. This work provides a detailed structural and mechanistic framework for the minimal TA protein insertion cycle.« less
  • This article reports on the mapping of the gene encoding the GPI-anchored membrane protein p137{sup GPI} (M11S1) to human chromosome 11p13. Genomic clones will help to discern the structure-activity relationships of the gene encoding this protein. 6 refs., 1 fig.