Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

2020 ◽  
Author(s):  
Tessa Sinnige
Keyword(s):  
Mitochondrial Protein ◽  
Methylglutaconic Aciduria

scholarly journals Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

2020 ◽  
Author(s):  
Ryan R. Cupo ◽  
James Shorter
Keyword(s):  
Atp Hydrolysis ◽  
Mitochondrial Protein ◽  
Mitochondrial Disorder ◽  
Mitochondrial Proteins ◽  
Protein Functionality ◽  
Mitochondrial Inner Membrane ◽  
Repeat Domain ◽  
Ankyrin Repeat Domain ◽  
Aaa Protein ◽  
Methylglutaconic Aciduria

ABSTRACTCells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human CLPB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 dissolves α-synuclein fibrils connected to Parkinson’s disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity. Thus, Skd3 is a potent protein disaggregase critical for human health.

scholarly journals Skd3 (human ClpB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ryan R Cupo ◽  
James Shorter
Keyword(s):  
Atp Hydrolysis ◽  
Mitochondrial Protein ◽  
Mitochondrial Disorder ◽  
Mitochondrial Proteins ◽  
Protein Functionality ◽  
Mitochondrial Inner Membrane ◽  
Repeat Domain ◽  
Ankyrin Repeat Domain ◽  
Aaa Protein ◽  
Methylglutaconic Aciduria

Cells have evolved specialized protein disaggregases to reverse toxic protein aggregation and restore protein functionality. In nonmetazoan eukaryotes, the AAA+ disaggregase Hsp78 resolubilizes and reactivates proteins in mitochondria. Curiously, metazoa lack Hsp78. Hence, whether metazoan mitochondria reactivate aggregated proteins is unknown. Here, we establish that a mitochondrial AAA+ protein, Skd3 (human ClpB), couples ATP hydrolysis to protein disaggregation and reactivation. The Skd3 ankyrin-repeat domain combines with conserved AAA+ elements to enable stand-alone disaggregase activity. A mitochondrial inner-membrane protease, PARL, removes an autoinhibitory peptide from Skd3 to greatly enhance disaggregase activity. Indeed, PARL-activated Skd3 solubilizes α-synuclein fibrils connected to Parkinson’s disease. Human cells lacking Skd3 exhibit reduced solubility of various mitochondrial proteins, including anti-apoptotic Hax1. Importantly, Skd3 variants linked to 3-methylglutaconic aciduria, a severe mitochondrial disorder, display diminished disaggregase activity (but not always reduced ATPase activity), which predicts disease severity. Thus, Skd3 is a potent protein disaggregase critical for human health.

Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation

2015 ◽  
Vol 38 (2) ◽  
pp. 211-219 ◽  
Author(s):  
Marta Kanabus ◽  
Rojeen Shahni ◽  
José W. Saldanha ◽  
Elaine Murphy ◽  
Vincent Plagnol ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Renal Cysts ◽  
Methylglutaconic Aciduria

Sirt5 Plays a Critical Role in Mitochondrial Protein Acylation and Mitochondrial Metabolic Homeostasis in Brown Fat

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 274-OR ◽  
Author(s):  
GUOXIAO WANG ◽  
JESSE G. MEYER ◽  
WEIKANG CAI ◽  
MENGYAO E. LI ◽  
SAMIR SOFTIC ◽  
...  
Keyword(s):  
Critical Role ◽  
Mitochondrial Protein ◽  
Brown Fat ◽  
Metabolic Homeostasis ◽  
Protein Acylation

Two HMG domains of yeast mitochondrial protein Abf2p have different affinity to DNA

2016 ◽  
pp. 62-65 ◽  
Author(s):  
A.V. Kurashenko ◽  
◽  
E.O. Samoilova ◽  
M.V. Balaeva ◽  
I.V. Chicherin ◽  
...  
Keyword(s):  
Mitochondrial Protein
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