5zf6
From Proteopedia
Crystal structure of the dimeric human PNPase
Structural highlights
DiseasePNPT1_HUMAN Combined oxidative phosphorylation defect type 13;Autosomal recessive nonsyndromic sensorineural deafness type DFNB. Combined oxidative phosphorylation deficiency 13 (COXPD13) [MIM:614932: A mitochondrial disorder characterized by early onset severe encephalomyopathy, dystonia, choreoathetosis, bucofacial dyskinesias and combined mitochondrial respiratory chain deficiency. Nerve conductions velocities are decreased. Levels of plasma and cerebrospinal fluid lactate are increased. Note=The disease is caused by mutations affecting the gene represented in this entry. Deafness, autosomal recessive, 70 (DFNB70) [MIM:614934: A form of non-syndromic deafness characterized by severe, bilateral hearing impairment with prelingual onset, resulting in inability to acquire normal speech. Note=The disease is caused by mutations affecting the gene represented in this entry. FunctionPNPT1_HUMAN RNA-binding protein implicated in numerous RNA metabolic processes. Hydrolyzes single-stranded polyribonucleotides processively in the 3'-to-5' direction. Mitochondrial intermembrane factor with RNA-processing exoribonulease activity. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double-stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Required for correct processing and polyadenylation of mitochondrial mRNAs. Plays a role as a cytoplasmic RNA import factor that mediates the translocation of small RNA components, like the 5S RNA, the RNA subunit of ribonuclease P and the mitochondrial RNA-processing (MRP) RNA, into the mitochondrial matrix. Plays a role in mitochondrial morphogenesis and respiration; regulates the expression of the electron transport chain (ETC) components at the mRNA and protein levels. In the cytoplasm, shows a 3'-to-5' exoribonuclease mediating mRNA degradation activity; degrades c-myc mRNA upon treatment with IFNB1/IFN-beta, resulting in a growth arrest in melanoma cells. Regulates the stability of specific mature miRNAs in melanoma cells; specifically and selectively degrades miR-221, preferentially. Plays also a role in RNA cell surveillance by cleaning up oxidized RNAs. Binds to the RNA subunit of ribonuclease P, MRP RNA and miR-221 microRNA.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] Publication Abstract from PubMedHuman polynucleotide phosphorylase (PNPase) is an evolutionarily conserved 3'-to-5' exoribonuclease principally located in mitochondria where it is responsible for RNA turnover and import. Mutations in PNPase impair structured RNA transport into mitochondria, resulting in mitochondrial dysfunction and disease. PNPase is a trimeric protein with a doughnut-shaped structure hosting a central channel for single-stranded RNA binding and degradation. Here, we show that the disease-linked human PNPase mutants, Q387R and E475G, form dimers, not trimers, and have significantly lower RNA binding and degradation activities compared to wild-type trimeric PNPase. Moreover, S1 domain-truncated PNPase binds single-stranded RNA but not the stem-loop signature motif of imported structured RNA, suggesting that the S1 domain is responsible for binding structured RNAs. We further determined the crystal structure of dimeric PNPase at a resolution of 2.8 A and, combined with small-angle X-ray scattering, show that the RNA-binding K homology and S1 domains are relatively inaccessible in the dimeric assembly. Taken together, these results show that mutations at the interface of the trimeric PNPase tend to produce a dimeric protein with destructive RNA-binding surfaces, thus impairing both of its RNA import and degradation activities and leading to mitochondria disorders. Crystal structure of dimeric human PNPase reveals why disease-linked mutants suffer from low RNA import and degradation activities.,Golzarroshan B, Lin CL, Li CL, Yang WZ, Chu LY, Agrawal S, Yuan HS Nucleic Acids Res. 2018 Jul 18. pii: 5055393. doi: 10.1093/nar/gky642. PMID:30020492[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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