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

Journal Article · · Molecular Cell

We discuss that mislocalized tail-anchored (TA) proteins of the outer mitochondrial membrane are cleared by a newly identified quality control pathway involving the conserved eukaryotic protein Msp1 (ATAD1 in humans). Msp1 is a transmembrane AAA-ATPase, but its role in TA protein clearance is not known. Here, using purified components reconstituted into proteoliposomes, we show that Msp1 is both necessary and sufficient to drive the ATP-dependent extraction of TA proteins from the membrane. A crystal structure of the Msp1 cytosolic region modeled into a ring hexamer suggests that active Msp1 contains a conserved membrane-facing surface adjacent to a central pore. Structure-guided mutagenesis of the pore residues shows that they are critical for TA protein extraction in vitro and for functional complementation of an msp1 deletion in yeast. Together, these data provide a molecular framework for Msp1-dependent extraction of mislocalized TA proteins from the outer mitochondrial membrane.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Contributing Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Grant/Contract Number:
AC02-06CH11357; NCI CCSG P30 CA060553; S10 RR029205; P41 GM103403; F32GM119194-01; T32 GM007183; 5T32CA9594-25; CCSG P30 CA060553
OSTI ID:
1461207
Alternate ID(s):
OSTI ID: 1390871
Journal Information:
Molecular Cell, Journal Name: Molecular Cell Vol. 67 Journal Issue: 2; ISSN 1097-2765
Publisher:
Cell Press - ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 70 works
Citation information provided by
Web of Science

References (54)

New heterologous modules for classical or PCR-based gene disruptions inSaccharomyces cerevisiae journal December 1994
Endoplasmic Reticulum Targeting and Insertion of Tail-Anchored Membrane Proteins by the GET Pathway journal August 2013
COPI selectively drives maturation of the early Golgi journal December 2015
ConSurf: Identification of Functional Regions in Proteins by Surface-Mapping of Phylogenetic Information journal January 2003
Nucleotide Binding and Conformational Switching in the Hexameric Ring of a AAA+ Machine journal April 2013
The GET Complex Mediates Insertion of Tail-Anchored Proteins into the ER Membrane journal August 2008
Substrate Recognition by AAA+ ATPases: Distinct Substrate Binding Modes in ATP-Dependent Protease Yme1 of the Mitochondrial Intermembrane Space journal January 2007
Deubiquitinases Sharpen Substrate Discrimination during Membrane Protein Degradation from the ER journal August 2013
How tails guide tail-anchored proteins to their destinations journal August 2007
Peripheral Protein Quality Control Removes Unfolded CFTR from the Plasma Membrane journal July 2010
Structural Insights into the Unusually Strong ATPase Activity of the AAA Domain of the Caenorhabditis elegans Fidgetin-like 1 (FIGL-1) Protein journal October 2013
Structural and mechanistic studies of VPS4 proteins journal September 2005
High resolution single particle refinement in EMAN2.1 journal May 2016
Phylogenetic analysis of AAA proteins journal April 2004
Bag6/Bat3/Scythe: A novel chaperone activity with diverse regulatory functions in protein biogenesis and degradation journal February 2013
A Ubiquitin Ligase-Associated Chaperone Holdase Maintains Polypeptides in Soluble States for Proteasome Degradation journal June 2011
Three new dominant drug resistance cassettes for gene disruption inSaccharomyces cerevisiae journal October 1999
BAG6/BAT3: emerging roles in quality control for nascent polypeptides journal December 2012
Secretion of a foreign protein from budding yeasts is enhanced by cotranslational translocation and by suppression of vacuolar targeting journal August 2014
Importing Mitochondrial Proteins: Machineries and Mechanisms journal August 2009
Comprehensive Characterization of Genes Required for Protein Folding in the Endoplasmic Reticulum journal March 2009
Meiotic Clade AAA ATPases: Protein Polymer Disassembly Machines journal May 2016
Membrane Protein Insertion at the Endoplasmic Reticulum journal November 2011
Atomic Structures of the Human Immunophilin FKBP-12 Complexes with FK506 and Rapamycin journal January 1993
Roles of the N domain of the AAA+ Lon protease in substrate recognition, allosteric regulation and chaperone activity: Proteolytic and chaperone activities of Lon journal November 2013
Scaling and assessment of data quality journal December 2005
Protein trafficking to plastids: one theme, many variations journal June 2008
Cellular Functions, Mechanism of Action, and Regulation of ftsh Protease journal October 2005
The conserved AAA-ATPase Msp1 confers organelle specificity to tail-anchored proteins journal May 2014
NIH Image to ImageJ: 25 years of image analysis journal June 2012
BAT3 Guides Misfolded Glycoproteins Out of the Endoplasmic Reticulum journal December 2011
Identification of a Targeting Factor for Posttranslational Membrane Protein Insertion into the ER journal March 2007
A class of membrane proteins with a C-terminal anchor journal March 1993
Identification of Candidate Substrates for the Golgi Tul1 E3 Ligase Using Quantitative diGly Proteomics in Yeast journal November 2014
Membrane protein turnover by the m ‐AAA protease in mitochondria depends on the transmembrane domains of its subunits journal July 2004
A Chaperone Cascade Sorts Proteins for Posttranslational Membrane Insertion into the Endoplasmic Reticulum journal October 2010
Quality control of inner nuclear membrane proteins by the Asi complex journal September 2014
Biogenesis of peroxisomes: Topogenesis of the peroxisomal membrane and matrix proteins journal April 2005
xia2 : an expert system for macromolecular crystallography data reduction journal December 2009
Mitochondrial proteases and protein quality control in ageing and longevity journal September 2015
Protein folding and quality control in the endoplasmic reticulum: Recent lessons from yeast and mammalian cell systems journal August 2011
Roles of multimerization and membrane association in the proteolytic functions of FtsH (HflB) journal August 2000
Targeting of C-Terminal (Tail)-Anchored Proteins: Understanding how Cytoplasmic Activities are Anchored to Intracellular Membranes journal January 2001
Features and development of Coot journal March 2010
Structure of the Get3 targeting factor in complex with its membrane protein cargo journal March 2015
M sp1/ ATAD 1 maintains mitochondrial function by facilitating the degradation of mislocalized tail‐anchored proteins journal May 2014
Tail-anchored membrane protein insertion into the endoplasmic reticulum journal November 2011
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Bipartite Signals Mediate Subcellular Targeting of Tail-anchored Membrane Proteins in Saccharomyces cerevisiae journal January 2003
Fast, scalable generation of high‐quality protein multiple sequence alignments using Clustal Omega journal January 2011
The AAA+ ATPase Thorase Regulates AMPA Receptor-Dependent Synaptic Plasticity and Behavior journal April 2011
Pore loops of the AAA+ ClpX machine grip substrates to drive translocation and unfolding journal October 2008
Protein quality control at the inner nuclear membrane journal December 2014
Intramitochondrial protein sorting. Isolation and characterization of the yeast MSP1 gene which belongs to a novel family of putative ATPases. journal November 1993