8v55 | pdb_00008v55

Human mitochondrial DNA polymerase gamma bound to a replication fork in an open conformation

spinqualitylabelsall models 8v55, resolution 4.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8v55 is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 4.2Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DPOG1_HUMAN Defects in POLG are the cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal dominant type 1 (PEOA1) [MIM:157640. Progressive external ophthalmoplegia is characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Defects in POLG are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions autosomal recessive (PEOB) [MIM:258450. PEOB is a severe form of progressive external ophthalmoplegia. It is clinically more heterogeneous than the autosomal dominant forms. Can be more severe. Defects in POLG are a cause of sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) [MIM:607459. SANDO is a systemic disorder resulting from mitochondrial dysfunction associated with mitochondrial depletion in skeletal muscle and peripheral nerve tissue. The clinical triad of symptoms consists of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis. However, the phenotype varies widely, even within the same family, and can also include myopathy, seizures, and hearing loss. An atypical form of the disease is characterized by headaches and/or seizures manifesting in childhood or adolescence, followed by development of cerebellar and sensory ataxia, dysarthria, progressive external ophthalmoplegia, and myoclonus in early adulthood. Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4A (MTDPS4A) [MIM:203700; also called Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis. An autosomal recessive hepatocerebral syndrome. The typical course of the disease includes severe developmental delay, intractable seizures, liver failure, and death in childhood. Refractory seizures, cortical blindness, progressive liver dysfunction, and acute liver failure after exposure to valproic acid are considered diagnostic features. The neuropathological hallmarks are neuronal loss, spongiform degeneration, and astrocytosis of the visual cortex. Liver biopsy results show steatosis, often progressing to cirrhosis. Defects in POLG are the cause of mitochondrial DNA depletion syndrome type 4B (MTDPS4B) [MIM:613662; also known as mitochondrial DNA depletion syndrome 4B MNGIE type or mitochondrial neurogastrointestinal encephalopathy syndrome POLG-related. An autosomal recessive progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility and pseudo-obstruction, cachexia, progressive external ophthalmoplegia, axonal sensory ataxic neuropathy, and muscle weakness. Defects in POLG are a cause of Leigh syndrome (LS) [MIM:256000. LS is a severe neurological disorder characterized by bilaterally symmetrical necrotic lesions in subcortical brain regions. Function DPOG1_HUMAN Involved in the replication of mitochondrial DNA. Associates with mitochondrial DNA. Publication Abstract from PubMed The replicative mitochondrial DNA polymerase, Polgamma, and its protein regulation are essential for the integrity of the mitochondrial genome. The intricacies of Polgamma regulation and its interactions with regulatory proteins, which are essential for fine-tuning polymerase function, remain poorly understood. Misregulation of the Polgamma heterotrimer, consisting of (i) PolG, the polymerase catalytic subunit and (ii) PolG2, the accessory subunit, ultimately results in mitochondrial diseases. Here, we used single particle cryo-electron microscopy to resolve the structure of PolG in its apoprotein state and we captured Polgamma at three intermediates within the catalytic cycle: DNA bound, engaged, and an active polymerization state. Chemical crosslinking mass spectrometry, and site-directed mutagenesis uncovered the region of LonP1 engagement of PolG, which promoted proteolysis and regulation of PolG protein levels. PolG2 clinical variants, which disrupted a stable Polgamma complex, led to enhanced LonP1-mediated PolG degradation. Overall, this insight into Polgamma aids in an understanding of mitochondrial DNA replication and characterizes how machinery of the replication fork may be targeted for proteolytic degradation when improperly functioning. Coordinated DNA polymerization by Polgamma and the region of LonP1 regulated proteolysis.,Riccio AA, Brannon AJ, Krahn JM, Bouvette J, Williams JG, Borgnia MJ, Copeland WC Nucleic Acids Res. 2024 Jun 27:gkae539. doi: 10.1093/nar/gkae539. PMID:38932681 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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