核糖核酸水解酶PNPase突變導致疾病之結構解析

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研究生：	郭巴耳 Golzarroshan, Bagher
論文名稱：	核糖核酸水解酶PNPase突變導致疾病之結構解析 Structural insights into the disease-linked human PNPase mutants in RNA binding and degradation
指導教授：	袁小琀 Yuan, Hanna 呂平江 Lyu, Ping-Chiang
口試委員:	蘇士哲 Sue, Shih-Che 殷献生 Yin, Hsien-Sheng 蕭傳鐙 Hsiao, Chwan-Deng
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	95
中文關鍵詞：	RNA 降解、粒線體RNA 導入、粒線體蛋白、核醣核酸酶、蛋白質結構
外文關鍵詞：	RNA decay, mitochondrial RNA import, mitochondrial proteins, exoribonuclease, crystal structure
相關次數：	點閱：3 下載：0
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Polynucleotide phosphorylase (PNPase) 是一演化上具高度保守性的核糖核酸外切酶，主要參與原核生物與真核生物中的RNA加工與降解作用。人類PNPase主要存在於粒線體中，除了參與RNA加工與降解作用之外，同時還參與引導具有結構的核糖核酸，進入粒線體基質 (mitochondria matrix) 中，包含5S rRNA, MRP RNA, RNase P RNA。PNPase的基因突變導致許多與人類粒線體功能缺失相關的疾病，突變造成粒線體內RNA分子的累積，或者破壞PNPase引導核糖核酸進入粒線體基質的功能。結晶學研究的結果已知PNPase為一三聚體環狀結構的蛋白，中間會形成一個單股RNA結合的通道，RNA的3端端點會由此通道被引導至PNPase的活性位置進行降解。然而目前對於疾病相關的基因突變，對PNPase蛋白的三級結構、四級結構的組成以及活性的影響仍並不清楚。
在本研究當中，我們發現一些疾病相關的胺基酸點突變，例如Q378R與E475G，會破壞PNPase的三聚體結構。具有這些突變的PNPase會形成二聚體結構，且對RNA結合與降解的活性較正常的PNPase活性低。此外，我們發現PNPase的S1結構區域主要負責結合具有結構的核糖核酸RNA的莖環 (stem-loop) 區域，而非RNA單股區域。我們更進一步解析了PNPase二聚體的晶體結構，結構的解析度為2.8 Å，其中的PNPase單體去除了S1結構區域並帶有N段組胺酸標籤 (His-Tag)。PNPase的結構顯示KH的活性區域，在二聚體的結構中比三聚體的結構更加封閉。我們也將二聚體以及三聚體的PNPase透過X光小角度散射 (Small-angle X-ray Scattering, SAXS) 實驗進行測定。結果顯示，S1活性區域在兩種結構當中位置變動性很大，可以看到開放與封閉的兩種構型。而在二聚體PNPase當中，S1活性域也較為封閉。實驗結果顯示，二聚體PNPase由於參與RNA結合的S1與KH的活性區域較為封閉，因此造成其與RNA的結合能力降低。總結上述的實驗結果，我們發現若胺基酸的點突變位於PNPase形成三聚體的結構中，單體與單體之間的交界處，則會造成PNPase趨向於形成二聚體的結構，並且形成較封閉的RNA結合通道。如此會導致PNPase對於RNA引導與降解的活性下降，進而造成粒線體功能異常與疾病。本研究也提供了治療與PNPase功能相關疾病的資訊以及可能的方法，例如藉由穩定PNPase三聚體的結構促進其RNA引導與降解的活性，而達到治療疾病的效果。

Polynucleotide phosphorylase (PNPase) is an evolutionary conserved 3'-to-5' exoribonuclease that functions in RNA processing and turnover in prokaryotes and eukaryotes. Human PNPase is mainly located in mitochondria where it not only participates in RNA processing and decay but it is also involved in importing a subgroup of structured RNAs, including 5S rRNA, MRP RNA, RNase P RNA and miRNAs, into the mitochondrial matrix. Mutations in PNPase that impair either mitochondrial RNA (mtRNA) degradation or RNA import are thus connected to mitochondrial dysfunctions and a wide spectrum of human diseases. Crystal structural studies reveal that PNPase is a trimeric protein assembled into a ring-like structure with a central channel for binding of a single-stranded RNA (ssRNA) and guiding its 3' end into the active site for degradation. However, it remained unclear how the disease-linked PNPase mutations affect protein folding, assembly and/or enzymatic activity.
In this study, we show that the trimeric assembly of PNPase is disrupted by the disease-linked mutations, including Q378R and E475G. PNPase is oligomerized into a dimeric conformation after introducing the disease-linked mutations, and these PNPase mutants exhibit lower RNA-binding and degrading activities as compared to the wild-type protein. Moreover, we found that S1 domain of PNPase is responsible for the interaction with the stem-loop motif of imported RNAs but it is not involved in binding to ssRNA. We further determined the crystal structure of the dimeric form of the S1 domain-truncated PNPase with an N-terminal His-tag at a resolution of 2.8 Å showing that the KH domains are less accessible in the dimeric form of PNPase. The overall structures of the full-length trimeric and dimeric forms of PNPase were further determined by small-angle X-ray scattering (SAXS), showing that S1 domains are flexible with open to closed conformations in both conformers and that S1 domains are not fully accessible in the dimeric structure. Taken together these results explain why these dimeric PNPase mutants with less accessible RNA-binding KH and S1 domains interact with RNA poorly. We thus conclude that mutations at the interface of the trimeric PNPase tend to produce a dimeric protein with obstructed RNA-binding surfaces, thus impairing both of its RNA import and degradation activities and leading to mitochondria dysfunction and diseases. This study provides a possible strategy for the treatment of PNPase-associated diseases by stabilizing the trimeric conformation of PNPase that could improve its functions in both RNA import and decay in mitochondria.

Acknowledgment……………...………..…………………………..…………..……II
中文摘要……………...……………………………………………..………………IV
Abstract……………………………...………………………………………..……..VI
Abbreviations………………………………………………………....…………..VIII
Table of Contents…………………..……………………………….……………..…X
1.    INTRODUCTION……………………………………………………...………..1
1.1.    RNA decay in mitochondria……………………………………….…………….2
1.2.    Macromolecules import into mitochondria……………………….……………..4
1.2.1.    Protein import into mitochondria…………………...…………….……………5
1.2.2.    RNA import into mitochondria………………………………….……………..6
1.3.    Biological functions of PNPase………………………………..….……………..9
1.3.1.    Knockdown studies……………………………………………….…………..10
1.3.2.    Overexpression studies……………………………………………………….11
1.4.    Domain organization and structure of PNPase………………….…..………….12
1.4.1.    RNase PH domains ………………………………..…………...…….……….13
1.4.2.    KH Domain …………………………………………………….……...……..14
1.4.3.    S1 Domain……………………………………………………………..……..15
1.5.    Disease-linked PNPase mutants……………………………..…………………16
1.6.    Objectives of this study………………………………………………..……….18
1.6.1.    Significance of the study…………………………………………….………..19
2.    MATERIALS AND METHODS………………………………….…….……..21
2.1.    PNPase gene cloning and expression…………………………………..……….22
2.1.1.    Construction of human PNPase expression vectors………………….……….22
2.1.2.    Site-directed mutagenesis of PNPase…………………………………...…….22
2.1.3.    Expression of PNPase proteins……………………………………………….23
2.1.4.    Protein purification……………………………………………………..…….24
2.2.    Characterization of PNPase oligomerization……………………….…..………25
2.2.1.    Gel filtration and multiangle-light scattering (MALS)………………..………25
2.3.    Measurement of protein melting points………………………………….……..26
2.4.    Ribonulease activity assays…………………………………………….………27
2.5.    RNA-binding assays……………………………………..…………….……….28
2.6.    Crystallization………………………………………………………….………29
2.7.    Crystal structure determination and refinement………………………….……..29
2.8.    SAXS analysis………………………………………………………....……….30
3.    RESULTS……………………………………………………………………….32
3.1.    Effects of disease-linked mutations on PNPase assembly and function...………33
3.1.1.    Disease-linked PNPase mutants are oligomerized into dimeric proteins……...33
3.1.2.    Dimeric and trimeric PNPase proteins have comparable thermal stability……35
3.1.3.    Dimeric PNPase mutants have reduced degradation activity…………...…….36
3.1.4.    Dimeric PNPase proteins have lower ssRNA binding and stem-loop RNA binding activities..………………………………………………….…………36
3.1.5.    S1 domain of PNPase interacts with the stem-loop RNA of imported RNAs…38
3.2.    Structural insights into the dimeric form of PNPase…………………..………..39
3.2.1.    Crystal structure of dimeric PNPase…………………………………….…….39
3.2.1.1.    Overall structure of dimeric PNPase……………………………..….………39
3.2.1.2.    GXXG motif in the dimeric structure …………………...………..…………41
3.2.2.    SAXS experiments………………………………………………….……..….41
3.2.2.1.    PNPase-∆S1 dimers share a similar quaternary structure………………...…41
3.2.2.2.    S1 domains in trimeric and dimeric PNPase structures……….….………….42
4.    DISSCUTION…………………………………………………………………..45
4.1.    PNPase mutants are primarily dimers but not functional trimeric proteins…......46
4.2.    KH pore is disrupted in dimeric forms of PNPase………………………....……47
4.3.    S1 pore is required for stem-loop RNA interactions……………………....……48
5.    FIGURES…………………………………………………………….…………51
Figure 1. mtDNA replication, transcription and translation……………………..…52
Figure 2. RNA import pathways into the human mitochondria…………………….53
Figure 3. Biological functions of human PNPase…………………………..………54
Figure 4. Crystal structures of PNPase and comparison to the structures of exosome……………………………………………………………..……………..55
Figure 5. Domain organization of PNPase…………………………………………56
Figure 6. The two disease-linked mutations, Q387R and E475G, are located in trimeric interfaces in PNPase…………………………………………………...….57
Figure 7. PNPase purification strategies………………………..………………….58
Figure 8. SDS-PAGE of PNPase………..………………….………………………59
Figure 9. Molar mass measurement of different forms of PNPase by SEC-MALS……………………………………………………………………………...60
Figure 10. Thermal stability of dimeric and trimeric PNPase proteins measured by DSF………………………………………………………………………..……….61
Figure 11. Disease-linked PNPase mutants exhibit lower RNA degradation activities……………………………………………………………………….…..62
Figure 12. Dimeric disease-linked PNPase proteins exhibit impaired RNA-binding activities…………….……………………………………………………………..63
Figure 13. Trimeric and dimeric forms of PNPase-NHis can be separated by reversed-phase chromatography………………………………………...…………64
Figure 14. The diffraction pattern of PNPase-∆S1-NHis…………………………..65
Figure 15. Two PNPase-∆S1-NHis protomers form a homodimer in the crystal…...66
Figure 16. The overall crystal structure of the dimeric form of PNPase-∆S1-NHis……………………………………………………………………………….67
Figure 17. The dimeric structure of PNPase-∆S1-NHis……………………………68
Figure 18. KH pore in dimeric structure is disrupted……………………………….69
Figure 19. Structural comparison reveals that protomers from dimeric and trimeric form of PNPase retained their overall structure………………………...…………..70
Figure 20. All dimeric PNPase-∆S1 proteins are folded into a similar overall structure……………………………………………………………………………71
Figure 21. SAXS profiles for full-length PNPase proteins…………....……………72
Figure 22. Kratky representation of experimental SAXS curves…………….……..73
Figure 23. EOM simulated curves and pools distribution………………...………..74
Figure 24. Representative models of dimeric and trimeric PNPase conformers generated by EOM………………………………………………………..………..75
Figure 25. The S1 pore in RNA exosomes and PNPase…….………………………76
6.    TABLES……………………………………………………………..………….77
Table 1. X-ray diffraction and refinement statistics for dimeric PNPase-∆S1-NHis……………………………………………………………………….………78
7.    REFERENCES………………………………………..………………………..79
8.    APPENDIX……………………………………………………………………..92
                                

Lykke-Andersen, S., et al., The eukaryotic RNA exosome: same scaffold but variable catalytic subunits. RNA Biol, 2011. 8(1): p. 61-6.
2. Carpousis, A.J., The RNA degradosome of Escherichia coli: an mRNA-degrading machine assembled on RNase E. Annu Rev Microbiol, 2007. 61: p. 71-87.
3. Cho, K.H., The Structure and Function of the Gram-Positive Bacterial RNA Degradosome. Front Microbiol, 2017. 8: p. 154.
4. Zinder, J.C. and C.D. Lima, Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors. Genes Dev, 2017. 31(2): p. 88-100.
5. Holt, I.J., et al., Mammalian mitochondrial nucleoids: organizing an independently minded genome. Mitochondrion, 2007. 7(5): p. 311-21.
6. Smeitink, J., L. van den Heuvel, and S. DiMauro, The genetics and pathology of oxidative phosphorylation. Nat Rev Genet, 2001. 2(5): p. 342-352.
7. Borowski, L.S., et al., RNA turnover in human mitochondria: More questions than answers? Biochim Biophs Acta, 2010. 1797(6-7): p. 1066-1070.
8. Ojala, D., J. Montoya, and G. Attardi, tRNA punctuation model of RNA processing in human mitochondria. Nature, 1981. 290(5806): p. 470-4.
9. Sanchez, M.I.G.L., et al., RNA processing in human mitochondria. Cell Cycle, 2011. 10(17): p. 2904-2916.
10. Clayton, D.A., Transcription and replication of animal mitochondrial DNAs. Int Rev Cytol, 1992. 141: p. 217-32.
11. Conrad-Webb, H., et al., The nuclear SUV3-1 mutation affects a variety of post-transcriptional processes in yeast mitochondria. Nucleic Acids Res, 1990. 18(6): p. 1369-76.
12. Dmochowska, A., P. Golik, and P.P. Stepien, The Novel Nuclear Gene Dss-1 of Saccharomyces-Cerevisiae Is Necessary for Mitochondrial Biogenesis. Curr Genet, 1995. 28(2): p. 108-112.
13. Gagliardi, D., et al., Messenger RNA stability in mitochondria: different means to an end. Trends Genet, 2004. 20(6): p. 260-7.
14. Dmochowska, A., et al., A human putative Suv3-like RNA helicase is conserved between Rhodobacter and all eukaryotes. Acta Biochim Polonica, 1999. 46(1): p. 155-162.
15. Minczuk, M., et al., Localisation of the human hSuv3p helicase in the mitochondrial matrix and its preferential unwinding of dsDNA. Nucleic Acids Res., 2002. 30(23): p. 5074-5086.
16. Shu, Z.Y., et al., Purified human SUV3p exhibits multiple-substrate unwinding activity upon conformational change. Biochemistry, 2004. 43(16): p. 4781-4790.
17. Szczesny, R.J., et al., Human mitochondrial RNA turnover caught in flagranti: involvement of hSuv3p helicase in RNA surveillance. Nucleic Acids Res, 2010. 38(1): p. 279-298.
18. Sarkar, D. and P.B. Fisher, Polynucleotide phosphorylase: An evolutionary conserved gene with an expanding repertoire of functions. Pharmacology & Therapeutics, 2006. 112(1): p. 243-263.
19. Mohanty, B.K. and S.R. Kushner, Polynucleotide phosphorylase functions both as a 3 '-> 5 ' exonuclease and a poly(A) polymerase in Escherichia coli. Proc Natl Acad Sci USA, 2000. 97(22): p. 11966-11971.
20. Borowski, L.S., et al., Human mitochondrial RNA decay mediated by PNPase-hSuv3 complex takes place in distinct foci. Nucleic Acids Res, 2013. 41(2): p. 1223-1240.
21. Bruni, F., et al., REXO2 Is an Oligoribonuclease Active in Human Mitochondria. Plos One, 2013. 8(5).
22. Wang, D.D.-H., et al., Human mitochondrial SUV3 and polynucleotide phosphorylase form a 330-kDa heteropentamer to cooperatively degrade double-stranded RNA with a 3-to-5 directionality. J Biol Chem., 2009. 284: p. 20812–20821.
23. Archibald, J.M., Endosymbiosis and Eukaryotic Cell Evolution. Curr Biol, 2015. 25(19): p. R911-R921.
24. Nunnari, J. and A. Suomalainen, Mitochondria: in sickness and in health. Cell, 2012. 148(6): p. 1145-59.
25. Taylor, S.W., et al., Characterization of the human heart mitochondrial proteome. Nat Biotechnol, 2003. 21(3): p. 281-286.
26. Kim, K.M., et al., Mitochondrial noncoding RNA transport. BMB Rep., 2017. 50(4): p. 164-174.
27. Wiedemann, N. and N. Pfanner, Mitochondrial machineries for protein import and assembly. Annu Rev Biochem, 2017. 86: p. 685-714.
28. Lithgow, T. and A. Schneider, Evolution of macromolecular import pathways in mitochondria, hydrogenosomes and mitosomes. Phil. Trans. R. Soc. B, 2010. 365(1541): p. 799-817.
29. Harbauer, A.B., et al., The Protein Import Machinery of Mitochondria-A Regulatory Hub in Metabolism, Stress, and Disease. Cell Metab, 2014. 19(3): p. 357-372.
30. Chacinska, A., et al., Importing Mitochondrial Proteins: Machineries and Mechanisms. Cell, 2009. 138(4): p. 628-644.
31. Hutu, D.P., et al., Mitochondrial protein import motor: Differential role of Tim44 in the recruitment of Pam17 and J-complex to the presequence translocase. Mol Biol Cell, 2008. 19(6): p. 2642-2649.
32. Gakh, E., P. Cavadini, and G. Isaya, Mitochondrial processing peptidases. Bioch Biophys Acta, 2002. 1592(1): p. 63-77.
33. Glick, B.S., et al., Cytochromes-C1 and Cytochromes-B2 Are Sorted to the Intermembrane Space of Yeast Mitochondria by a Stop-Transfer Mechanism. Cell, 1992. 69(5): p. 809-822.
34. Rainey, R.N., et al., A new function in translocation for the mitochondrial i-AAA protease Yme1: Import of polynucleotide phosphorylase into the intermembrane space. Mol Cell Biol, 2006. 26(22): p. 8488-8497.
35. Rubio, M.A.T., et al., Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import. Proc Natl Acad Sci USA, 2008. 105(27): p. 9186-9191.
36. Martin, R.P., et al., Import of Nuclear Deoxyribonucleic-Acid Coded Lysine-Accepting Transfer Ribonucleic-Acid (Anticodon C-U-U) into Yeast Mitochondria. Biochemistry, 1979. 18(21): p. 4600-4605.
37. LeBlanc, A.J., A.E. Yermovsky-Kammerer, and S.L. Hajduk, A nuclear encoded and mitochondrial imported dicistronic tRNA precursor in Trypanosoma brucei. J Biol Chem, 1999. 274(30): p. 21071-21077.
38. Kolesnikova, O.A., et al., Nuclear DNA-encoded tRNAs targeted into mitochondria can rescue a mitochondrial DNA mutation associated with the MERRF syndrome in cultured human cells. Hum Mol Gen, 2004. 13(20): p. 2519-2534.
39. Kamenski, P., et al., tRNA mitochondrial import in yeast: Mapping of the import determinants in the carrier protein, the precursor of mitochondrial lysyl-tRNA synthetase. Mitochondrion, 2010. 10(3): p. 284-293.
40. Tarassov, I., N. Entelis, and R.P. Martin, An Intact Protein Translocating Machinery Is Required for Mitochondrial Import of a Yeast Cytoplasmic Transfer-Rna. J Mol Biol, 1995. 245(4): p. 315-323.
41. Gowher, A., et al., Induced tRNA Import into Human Mitochondria: Implication of a Host Aminoacyl-tRNA-Synthetase. Plos One, 2013. 8(6).
42. Wang, G., et al., PNPASE and RNA trafficking into mitochondria. Biochim. Biophys. Acta Gene Reg Mech., 2012. 1819(9-10): p. 998-1007.
43. Kren, B.T., et al., microRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biol, 2009. 6(1): p. 65-72.
44. Smirnov, A.V., et al., Specific Features of 5S rRNA Structure - Its Interactions with Macromolecules and Possible Functions. Biochemistry (Moscow), 2008. 73(13): p. 1418.
45. Doersen, C.J., et al., Characterization of an Rnase P-Activity from Hela-Cell Mitochondria - Comparison with the Cytosol Rnase P-Activity. J Biol Chem, 1985. 260(10): p. 5942-5949.
46. Chang, D.D. and D.A. Clayton, Mouse RNAase MRP RNA is encoded by a nuclear gene and contains a decamer sequence complementary to a conserved region of mitochondrial RNA substrate. Cell, 1989. 56(1): p. 131-9.
47. Puranam, R.S. and G. Attardi, The RNase P associated with HeLa cell mitochondria contains an essential RNA component identical in sequence to that of the nuclear RNase P. Mol Cellular Biol, 2001. 21(2): p. 548-561.
48. MacFarlane, L.A. and P.R. Murphy, MicroRNA: Biogenesis, Function and Role in Cancer. Curr Genomics, 2010. 11(7): p. 537-561.
49. Magalhaes, P.J., A.L. Andreu, and E.A. Schon, Evidence for the presence of 5S rRNA in mammalian mitochondria. Mol Biol Cell, 1998. 9(9): p. 2375-2382.
50. Smirnov, A., et al., Mitochondrial Enzyme Rhodanese Is Essential for 5 S Ribosomal RNA Import into Human Mitochondria. J Biol Chem, 2010. 285(40): p. 30792-30803.
51. Wang, G., et al., PNPASE regulates RNA import into mitochondria. Mol Cell, 2010. 142(3): p. 456-67.
52. Barrey, E., et al., Pre-microRNA and Mature microRNA in Human Mitochondria. Plos One, 2011. 6(5).
53. Leszczyniecka, M., et al., Expression regulation and genomic organization of human polynucleotide phosphorylase, hPNPase(old-35), a Type I interferon inducible early response gene. Gene, 2003. 316: p. 143-156.
54. Leszczyniecka, M., et al., Identification and cloning of human polynucleotide phosphorylase, hPNPase(')(old-35) in the context of terminal differentiation and cellular senescence. Proc Natl Acad Sci USA, 2002. 99(26): p. 16636-16641.
55. Seth, R.B., et al., Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell, 2005. 122(5): p. 669-82.
56. Chen, H.W., et al., Mammalian polynucleotide phosphorylase is an intermembrane space RNase that maintains mitochondrial homeostasis. Mol Cell Biol, 2006. 26(22): p. 8475-8487.
57. Shepherd, D.L., et al., Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase). J Mol Cell Cardiol, 2017. 110: p. 15-25.
58. Sarkar, D., et al., Down-regulation of myc as a potential target for growth arrest induced by human polynucleotide phosphorylase (hPNPase(old-35)) in human melanoma cells. J Biol Chem, 2003. 278(27): p. 24542-24551.
59. Sarkar, D., E.S. Park, and P.B. Fisher, Defining the mechanism by which IFN-beta dowregulates c-myc expression in human melanoma cells: pivotal role for human polynucleotide phosphorylase (hPNPase(old-35)). Cell Death Differ, 2006. 13(9): p. 1541-1553.
60. French, S.W., et al., The TCL1 oncoprotein binds the RNase PH domains of the PNPase exoribonuclease without affecting its RNA degrading activity. Cancer Lett, 2007. 248(2): p. 198-210.
61. Sarkar, D., et al., Activation of double-stranded RNA-dependent protein kinase, a new pathway by which human polynucleotide phosphorylase (hPNPase(old-35)) induces apoptosis. Cancer Res, 2007. 67(17): p. 7948-7953.
62. Finkel, T. and N.J. Holbrook, Oxidants, oxidative stress and the biology of ageing. Nature, 2000. 408(6809): p. 239-247.
63. Sarkar, D. and P.B. Fisher, Molecular mechanisms of aging-associated inflammation. Cancer Lett, 2006. 236(1): p. 13-23.
64. Sarkar, D., et al., Human polynucleotide phosphorylase (hPNPase(old-35)): A potential link between aging and inflammation. Cancer Res, 2004. 64(20): p. 7473-7478.
65. Das, S.K., et al., Human polynucleotide phosphorylase (hPNPaseold-35): an evolutionary conserved gene with an expanding repertoire of RNA degradation functions. Oncogene, 2011. 30: p. 1733-1743.
66. Symmons, M.F., G.H. Jones, and B.F. Luisi, A duplicated fold is the structural basis for polynucleotide phosphorylase catalytic activity, processivity, and regulation. Structure, 2000. 8: p. 1215-1226.
67. Schuster, G. and D. Stern, RNA polyadenylation and decay in mitochondria and chloroplasts. Prog. Mol. Biol. Transl. Sci., 2009. 85: p. 393-422.
68. Lin, C.L., et al., Crystal structure of human polynucleotide phosphorylase: insights into its domain function in RNA binding and degradation. Nucleic Acids Res, 2012. 40(9): p. 4146-57.
69. Evguenieva-Hackenberg, E., et al., An exosome-like complex in Sulfolobus solfataricus. Embo Rep, 2003. 4(9): p. 889-893.
70. Mitchell, P., et al., The exosome: A conserved eukaryotic RNA processing complex containing multiple 3'->5' exoribonucleases. Cell, 1997. 91(4): p. 457-466.
71. Deutscher, M.P., G.T. Marshall, and H. Cudny, Rnase Ph - an Escherichia-Coli Phosphate-Dependent Nuclease Distinct from Polynucleotide Phosphorylase. Proc Natl Acad Sci USA, 1988. 85(13): p. 4710-4714.
72. Leszczyniecka, M., et al., The origin of polynucleotide phosphorylase domains. Mol Phylogenetics Evol, 2004. 31(1): p. 123-130.
73. Portnoy, V., et al., Analysis of the human polynucleotide phosphorylase (PNPase) reveals differences in RNA binding and response to phosphate compared to its bacterial and chloroplast counterparts. RNA, 2008. 14(2): p. 297-309.
74. Nurmohamed, S., et al., Crystal structure of Escherichia coli polynucleotide phosphorylase core bound to RNase E, RNA and manganese: implications for catalytic mechanism and RNA degradosome assembly. J Mol Biol, 2009. 389(1): p. 17-33.
75. Siomi, H., et al., The pre-mRNA binding K protein contains a novel evolutionarily conserved motif. Nucleic Acids Res, 1993. 21(5): p. 1193-8.
76. Valverde, R., L. Edwards, and L. Regan, Structure and function of KH domains. FEBS J, 2008. 275(11): p. 2712-26.
77. Matus-Ortega, M.E., et al., The KH and S1 domains of Escherichia coli polynucleotide phosphorylase are necessary for autoregulation and growth at low temperature. Biochim Biophys Acta, Gene Structure and Expression, 2007. 1769(3): p. 194-203.
78. Grishin, N.V., KH domain: one motif, two folds. Nucleic Acids Res, 2001. 29(3): p. 638-643.
79. Oddone, A., et al., Structural and biochemical characterization of the yeast exosome component Rrp40. Embo Reports, 2007. 8(1): p. 63-69.
80. Shi, Z., et al., Crystal structure of Escherichia coli PNPase: central channel residues are involved in processive RNA degradation. RNA, 2008. 14(11): p. 2361-71.
81. Hardwick, S.W., et al., Crystal structure of Caulobacter crescentus polynucleotide phosphorylase reveals a mechanism of RNA substrate channelling and RNA degradosome assembly. Open Biol, 2012. 2(4): p. 120028.
82. Subramanian, A.R., Structure and functions of ribosomal protein S1. Prog Nucleic Acid Res Mol Biol, 1983. 28: p. 101-142.
83. Bycroft, M., et al., The solution structure of the S1 RNA binding domain: A member of an ancient nucleic acid–binding fold. Cell, 1997. 88: p. 235-242.
84. Schubert, M., et al., Structural characterization of the RNase E S1 domain and identification of its oligonucleotide-binding and dimerization Interfaces. J Mol Biol., 2004. 341: p. 37-54.
85. Chu, L.-Y., et al., Structural insights into RNase R in RNA unwinding and degradation. Nucleic Acids Res, 2017. 45: p. 12015–12024.
86. Sarkar, D., et al., Defining the domains of human polynucleotide phosphorylase (hPNPase(OLD-35)) mediating cellular senescence. Mol Cell Biol, 2005. 25(16): p. 7333-7343.
87. Stickney, L.M., et al., Function of the conserved S1 and KH domains in polynucleotide phosphorylase. J Bacteriol, 2005. 187(21): p. 7214-21.
88. Singh, B., J.S. Modica-Napolitano, and K.K. Singh, Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome. Semin Cancer Biol, 2017. 47: p. 1-17.
89. Roger, A.J., S.A. Munoz-Gomez, and R. Kamikawa, The Origin and Diversification of Mitochondria. Curr Biol, 2017. 27(21): p. R1177-R1192.
90. Mishra, P., Interfaces between mitochondrial dynamics and disease. Cell Calcium, 2016. 60(3): p. 190-198.
91. Kang, Y.L., L.F. Fielden, and D. Stojanovski, Mitochondrial protein transport in health and disease. Semin Cell Devel Biol, 2018. 76: p. 142-153.
92. El-Hattab, A.W., et al., Therapies for mitochondrial diseases and current clinical trials. Mol Genet Metab, 2017. 122(3): p. 1-9.
93. Schapira, A.H.V., Mitochondrial disease. Lancet, 2006. 368(9529): p. 70-82.
94. Ameln, S.v., et al., A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss. Am J Human Genet, 2012. 91: p. 1-9.
95. Vedrenne, V., et al., Mutation in PNPT1, which encodes a polyribonucleotide nucleotidyltransferase, impairs RNA import into mitochondria and causes respiratory-chain deficiency. Am J Hum Genet, 2012. 91(5): p. 912-918.
96. Alodaib, A., et al., Whole-exome sequencing identifies novel variants in PNPT1 causing oxidative phosphorylation defects and severe multisystem disease. Eur J Hum Genet, 2017. 25(1): p. 79-84.
97. Matilainen, S., et al., Defective mitochondrial RNA processing due to PNPT1 variants causes Leigh syndrome. Hum Mol Genet, 2017. 26(17): p. 3352-3361.
98. Sato, R., et al., Novel biallelic mutations in the PNPT1 gene encoding a mitochondrial-RNA-import protein PNPase cause delayed myelination. Clin Genet, 2018. 93(2): p. 242-247.
99. Kopec, J. and G. Schneider, Comparison of fluorescence and light scattering based methods to assess formation and stability of protein-protein complexes. J Struct Biol, 2011. 175(2): p. 216-23.
100. Otwinowski, Z. and W. Minor, Processing of X-ray diffraction data collected in oscillation mode. Macromolecular Crystallography, Pt A, 1997. 276: p. 307-326.
101. Franke, D., et al., ATSAS 2.8: a comprehensive data analysis suite for small-angle scattering from macromolecular solutions. J Appl Crystallogr, 2017. 50: p. 1212-1225.
102. Franklin, M.C., et al., Structural genomics for drug design against the pathogen Coxiella burnetii. Proteins, 2015. 83(12): p. 2124-36.
103. Receveur-Brechot, V. and D. Durand, How Random are Intrinsically Disordered Proteins? A Small Angle Scattering Perspective. Curr Protein Pept Sci, 2012. 13(1): p. 55-75.
104. Franke, D. and D.I. Svergun, DAMMIF, a program for rapid ab-initio shape determination in small-angle scattering. J Appl Crystallogr, 2009. 42: p. 342-346.
105. Vedrenne, V., et al., Mutation in PNPT1, which encodes a polyribonucleotide nucleotidyltransferase, impairs RNA import into mitochondria and causes respiratory-chain deficiency. Am J Human Genet, 2012. 91: p. 912-918.
106. von Ameln, S., et al., A Mutation in PNPT1, Encoding Mitochondrial-RNA-Import Protein PNPase, Causes Hereditary Hearing Loss. Am J Hum Genet, 2012. 91(5): p. 919-927.
107. Buttner, K., K. Wenig, and K.P. Hopfner, Structural framework for the mechanism of archaeal exosomes in RNA processing. Mol Cell, 2005. 20(3): p. 461-471.
108. Liu, Q.S., J.C. Greimann, and C.D. Lima, Reconstitution, activities, and structure of the eukaryotic RNA exosome (vol 127, pg 1223, 2006). Cell, 2007. 131(1): p. 188-189.
109. Makino, D.L., M. Baumgartner, and E. Conti, Crystal structure of an RNA-bound 11-subunit eukaryotic exosome complex. Nature, 2013. 495(7439): p. 70-5.
110. Zinder, J.C., E.V. Wasmuth, and C.D. Lima, Nuclear RNA Exosome at 3.1 angstrom Reveals Substrate Specificities, RNA Paths, and Allosteric Inhibition of Rrp44/Dis3. Mol Cell, 2016. 64(4): p. 734-745.
111. Pearce, S.F., et al., Regulation of Mammalian Mitochondrial Gene Expression: Recent Advances. Trends Biochem Sci, 2017. 42(8): p. 625-639.
112. Kim, K.M., et al., Mitochondrial noncoding RNA transport. Bmb Reports, 2017. 50(4): p. 164-174.
113. Sokhi, U.K., et al., Human Polynucleotide Phosphorylase (hPNPaseold-35): Should I Eat You or Not-That Is the Question? Adv Cancer Res, Vol 119, 2013. 119: p. 161-190.
114. Lin-Chao, S., N.T. Chiou, and G. Schuster, The PNPase, exosome and RNA helicases as the building components of evolutionarily-conserved RNA degradation machines. J Biomed Sci, 2007. 14: p. 523-32.

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