TY - JOUR
T1 - Mitochondrial mislocalization and altered assembly of a cluster of Barth syndrome mutant tafazzins
AU - Claypool, Steven M.
AU - McCaffery, J. Michael
AU - Koehler, Carla M.
N1 - Funding Information:
Yuka Kushida’s visit to the Western Australia Museum was supported by funding from Okinawa Research Core for Highly Innovative Discipline Science from the University of the Ryukyus. The sub-Antarctic specimens were collected by the ACE expedition supported by the ACE Foundation and Ferring Pharmaceuticals and supplied by the Western Australian Museum. This work was supported by the research project Tohoku Ecosystem-Associated Marine Sciences from the Ministry of Education, Culture, Sports, Science, and Technology (grant Number: JPMXD1111105260) and the common university budget of James Davis Reimer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2006/7/31
Y1 - 2006/7/31
N2 - None of the 28 identified point mutations in tafazzin (Taz1p), which is the mutant gene product associated with Barth syndrome (BTHS), has a biochemical explanation. In this study, endogenous Taz1p was localized to mitochondria in association with both the inner and outer mitochondrial membranes facing the intermembrane space (IMS). Unexpectedly, Taz1p does not contain transmembrane (TM) segments. Instead, Taz1p membrane association involves a segment that integrates into, but not through, the membrane bilayer. Residues 215-232, which were predicted to be a TM domain, were identified as the interfacial membrane anchor by modeling four distinct BTHS mutations that occur at conserved residues within this segment. Each Taz1p mutant exhibits altered membrane association and is nonfunctional. However, the basis for Taz1p dysfunction falls into the following two categories: (1) mistargeting to the mitochondrial matrix or (2) correct localization associated with aberrant complex assembly. Thus, BTHS can be caused by mutations that alter Taz1p sorting and assembly within the mitochondrion, indicating that the lipid target of Taz1p is resident to IMS-facing leaflets.
AB - None of the 28 identified point mutations in tafazzin (Taz1p), which is the mutant gene product associated with Barth syndrome (BTHS), has a biochemical explanation. In this study, endogenous Taz1p was localized to mitochondria in association with both the inner and outer mitochondrial membranes facing the intermembrane space (IMS). Unexpectedly, Taz1p does not contain transmembrane (TM) segments. Instead, Taz1p membrane association involves a segment that integrates into, but not through, the membrane bilayer. Residues 215-232, which were predicted to be a TM domain, were identified as the interfacial membrane anchor by modeling four distinct BTHS mutations that occur at conserved residues within this segment. Each Taz1p mutant exhibits altered membrane association and is nonfunctional. However, the basis for Taz1p dysfunction falls into the following two categories: (1) mistargeting to the mitochondrial matrix or (2) correct localization associated with aberrant complex assembly. Thus, BTHS can be caused by mutations that alter Taz1p sorting and assembly within the mitochondrion, indicating that the lipid target of Taz1p is resident to IMS-facing leaflets.
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U2 - 10.1083/jcb.200605043
DO - 10.1083/jcb.200605043
M3 - Article
C2 - 16880272
AN - SCOPUS:33746606474
SN - 0021-9525
VL - 174
SP - 379
EP - 390
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 3
ER -