The mammalian protein MTCH1 can function as an insertase DOI Creative Commons

Anna Roza Dimogkioka,

A. Elias, Doron Rapaport

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 13, 2024

The outer mitochondrial membrane (OMM) hosts a variety of proteins such as import machineries, enzymes, fission/fusion factors, and pore proteins. In Saccharomyces cerevisiae, the MIM complex, consisting Mim1 Mim2, mediates insertion α-helical into OMM. Until recently, it was unclear which serve this function in higher eukaryotes. Recent studies identified MTCH2 insertase OMM mammals. MTCH1 is paralogue but its general contribution to biogenesis process are not clear. To better characterize MTCH1, we explored whether or could functionally replace Mim1/Mim2 yeast. Expression yeast cells lacking Mim1, both revealed that MTCH2, compensate growth defects upon deleting complex. Furthermore, restore substrates, TOM complex stability, morphology mitochondria. These findings indicate by itself has activity functional homologue despite absence any evolutionary relation between mammalian insertases.

Язык: Английский

Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin DOI Creative Commons
Jeong Hyun Oh,

Christy Catherine,

Eun Seon Kim

и другие.

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 17, 2025

Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington's disease (HD). Since no current treatment delays the progression of HD, we develop a mechanistic approach to prevent mutant huntingtin (mHttex1) aggregation. Here, engineer ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins peroxisomes, remove mHttex1 aggregates. Using yeast toxicity-based screening random library, identify two PEX19 variants and equivalent mutations into human (hsPEX19). These effectively delay aggregation in vitro cellular HD models. The mutated hydrophobic residue α4 helix hsPEX19 binds N17 domain mHttex1, thereby inhibiting initial process. Overexpression hsPEX19-FV variant rescues HD-associated phenotypes primary striatal neurons Drosophila. Overall, our data reveal that engineering chaperones is promising therapeutic for rational targeting HD.

Язык: Английский

Процитировано

0
The nascent polypeptide-associated complex (NAC) as regulatory hub on ribosomes DOI
Laurenz Rabl, Elke Deuerling

Biological Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Abstract The correct synthesis of new proteins is essential for maintaining a functional proteome and cell viability. This process tightly regulated, with ribosomes associated protein biogenesis factors ensuring proper production, modification, targeting. In eukaryotes, the conserved nascent polypeptide-associated complex (NAC) plays central role in coordinating early processing by regulating ribosome access multiple factors. NAC recruits modifying enzymes to ribosomal exit site N-terminus directs secretory into SRP-mediated targeting pathway. this review we will focus on these pathways, which are critical summarize recent advances understanding cotranslational functions mechanisms higher eukaryotes.

Язык: Английский

Процитировано

0
Chaperone-mediated insertion of mitochondrial import receptor TOM70 protects against diet-induced obesity DOI
Pedro Latorre‐Muro, Tevis Vitale, M. Ravichandran

и другие.

Nature Cell Biology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Язык: Английский

Процитировано

0
Engineering a membrane protein chaperone to ameliorate the proteotoxicity of mutant huntingtin DOI Creative Commons
Hyun-Ju Cho, Jeonghyun Oh,

Christy Catherine

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Май 17, 2024

Abstract Toxic protein aggregates are associated with various neurodegenerative diseases, including Huntington’s disease (HD). Since no current treatment delays the progression of HD, we developed a mechanistic approach to preventing mutant huntingtin (mHttex1) aggregation. Here, engineered ATP-independent cytosolic chaperone PEX19, which targets peroxisomal membrane proteins peroxisomes, remove mHttex1 aggregates. Using yeast toxicity-based screening random library, identified two PEX19 (scPEX19) variants and equivalent mutations into human (hsPEX19). These prevented aggregationin vitroand in cellular HD models. The mutated hydrophobic residue α4 helix ofhsPEX19 binds N17 domain mHttex1, thereby inhibiting initial aggregation process. Overexpression thehsPEX19-FV variant rescues HD-associated phenotypes primary striatal neurons inDrosophila. Overall, our data reveal that engineering chaperones is promising therapeutic for rational targeting HD.

Язык: Английский

Процитировано

0
A chaperone-assisted mechanism of outer mitochondrial membrane TOM70 insertion protective against diet-induced obesity DOI Creative Commons
Pedro Latorre‐Muro, Tevis Vitale, M. Ravichandran

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Авг. 1, 2024

Abstract Outer mitochondrial membrane (OMM) proteins communicate with the cytosol and other organelles including endoplasmic reticulum (ER)1,2. This communication is important in thermogenic adipocytes to increase energy expenditure that controls body temperature weight3,4. However, regulatory mechanisms of OMM protein insertion are poorly understood. Herein, stress-induced cytosolic chaperone PPID (peptidyl-prolyl isomerase D/cyclophilin 40/Cyp40) drives import receptor TOM70 regulating weight obese mice, respiratory/thermogenic function brown adipocytes. PPIase activity C-terminal tetratricopeptide repeats (TPR), which show specificity towards core C-tail domains, facilitate insertion. Our results provide an unprecedented role for ER-stress-activated chaperones controlling metabolism through a selective mechanism implications adaptation cold temperatures high-calorie diets.

Язык: Английский

Процитировано

0
Functional similarities and differences among subunits of the nascent polypeptide-associated complex (NAC) of Saccharomyces cerevisiae DOI Creative Commons
Brenda Schilke,

Thomas Ziegelhoffer,

Przemyslaw Domanski

и другие.

Cell Stress and Chaperones, Год журнала: 2024, Номер 29(6), С. 721 - 734

Опубликована: Окт. 18, 2024

Protein factors bind ribosomes near the tunnel exit, facilitating protein trafficking and folding. In eukaryotes, heterodimeric nascent polypeptide-associated complex (NAC) is most abundant-equimolar to ribosomes. Saccharomyces cerevisiae has a minor β-type subunit (Nacβ2) in addition abundant Nacβ1, therefore two NAC heterodimers, α/β1 α/β12. The additional beta gene arose at time of whole genome duplication that occurred S. lineage. Nacβ2 been implicated regulating fate messenger RNA encoding ribosomal Rpl4 during translation via its interaction with Caf130 regulatory CCR4-Not complex. We found residues just C-terminal globular domain are required for negative effect on growth cells lacking Acl4, specialized chaperone Rpl4. Substitution these homologous positions Nacβ1 results chimeric interacts slows ∆acl4 Nacβ2. Furthermore, alteration N-terminus or previously shown affect ribosome binding overcomes defect ∆acl4. Our consistent model which Nacβ2's association per se precise positioning necessary productive recruitment drive degradation.

Язык: Английский

Процитировано

0
The mammalian protein MTCH1 can function as an insertase DOI Creative Commons

Anna Roza Dimogkioka,

A. Elias, Doron Rapaport

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 13, 2024

The outer mitochondrial membrane (OMM) hosts a variety of proteins such as import machineries, enzymes, fission/fusion factors, and pore proteins. In Saccharomyces cerevisiae, the MIM complex, consisting Mim1 Mim2, mediates insertion α-helical into OMM. Until recently, it was unclear which serve this function in higher eukaryotes. Recent studies identified MTCH2 insertase OMM mammals. MTCH1 is paralogue but its general contribution to biogenesis process are not clear. To better characterize MTCH1, we explored whether or could functionally replace Mim1/Mim2 yeast. Expression yeast cells lacking Mim1, both revealed that MTCH2, compensate growth defects upon deleting complex. Furthermore, restore substrates, TOM complex stability, morphology mitochondria. These findings indicate by itself has activity functional homologue despite absence any evolutionary relation between mammalian insertases.

Язык: Английский

Процитировано

0