LONP1 explained

Lon protease homolog, mitochondrial is a protease, an enzyme that in humans is encoded by the LONP1 gene.[1] [2] [3] [4]

Structure

The nuclear-gene encoded mitochondrial matrix LON peptidase 1 (LONP1), originally thought to be responsible for protein quality control (PQC) by degrading unfolded or misfolded proteins, has several essential functions like proteolytic activity, chaperone activity and mitochondrial DNA (mtDNA) regulation. Lon protease is a member of ATP-dependent proteases (AAA+ proteases). Mature LONP1 is catalytically active in its homohexameric structure, while other formations of complexes have been observed such as the homoheptameric ring in Saccharomyces cerevisiae. A single subunit of LONP1 consists of three domains: The N-domain for substrate recognition and binding, an AAA + module (A-domain) for ATP binding and hydrolysis, and a P-domain for protein proteolysis. A homologous protease to LONP1 expressed in E.coli. regulates gene expression by targeting specific regulatory proteins for degradation. Moreover, LONP1 is able to bind a specific sequence in the light and heavy chain promoters of the mitochondrial genome which are involved in regulation of mtDNA replication and transcription.

Function

Lon protease (LONP1) is a conserved serine peptidase identified from bacteria to eukaryotic cells.[5] In mitochondrial matrix, a majority of damaged proteins is removed via proteolysis led by Lon protease, which is an essential mechanism for mitochondrial protein quality control. LONP1 is the major protease responsible for the recognition and removal of unfolded proteins in the mitochondrial matrix and thereby protects the cell from the accumulation of aggregated proteins in the mitochondrion.[6] However LONP1 is unable to recognise or degrade model aggregated proteins.

For Lon protease-dependent degradation, protein substrates are first recognized and then unfolded if necessary in an ATP-dependent manner. The substrates are subsequently transferred through the pore of complex and into the proteolytic chamber of complex for degradation. ATP binding to the AAA module of the Lon complex results in a change in Lon conformation into a proteolytically active state. In general, Lon protease interacts with peptide regions(sequences) that are located within the hydrophobic core of substrates and rarely on the surface. These regions can be presented to Lon protease when proteins are damaged and lost their conformation integrity.[7] In addition to misfolded proteins, several regulatory proteins can be processed by Lon protease by removing a degradable tag before they fully gain their biological functions.[8]

LONP1 is also a DNA-binding protein that participates in mtDNA maintenance and gene expression regulation.[9] LONP1 degrades mitochondrial transcription factor A (TFAM) when substrate is modified by post-translational modifications (PTMs) such as phosphorylation, regulating mtDNA copy number and metabolism to maintain the TFAM/mtDNA ratio necessary to control replication and transcription.[10]

Clinical significance and genetic deficiency

Given the crucial role of LON protease in maintaining the control of mitochondrial function,[11] its dynamics in expression under stress conditions has been found associating with human diseases and aging.[12] [13] For example, LONP1 expression levels are increased in different tumors and tumor cell lines. Downregulation of LONP1 in some tumor cells causes apoptosis and cell death, indicating a possible addiction of tumor cells to LONP1 function, as occurs with other intracellular proteases associated with cancer.In addition, genetic deficiency of LONP1, caused by biallelic deleterious variants in the LONP1 gene, result in a pattern of severe congenital anomalies called the CODAS syndrome[14] [15] for "Cerebral, ocular, dental, auricular, skeletal anomalies.[16] Thus, LONP1 seems to have important functions in developmental processes that had not been predicted from the previous studies in cell culture models. A study published in 2021 has suggested that genetic variants in LONP1 may be a predisposing factor to the development of congenital diaphragmatic hernia.[17] highlighting yet another role of LONP1 in human embryonic/fetal development.

See also

Further reading

Notes and References

  1. Wang N, Gottesman S, Willingham MC, Gottesman MM, Maurizi MR . A human mitochondrial ATP-dependent protease that is highly homologous to bacterial Lon protease . Proceedings of the National Academy of Sciences of the United States of America . 90 . 23 . 11247–51 . December 1993 . 8248235 . 47959 . 10.1073/pnas.90.23.11247 . 1993PNAS...9011247W . free .
  2. Petukhova GV, Grigorenko VG, Lykov IP, Yarovoi SV, Lipkin VM, Gorbalenya AE . Cloning and sequence analysis of cDNA for a human homolog of eubacterial ATP-dependent Lon proteases . FEBS Letters . 340 . 1–2 . 25–8 . February 1994 . 8119403 . 10.1016/0014-5793(94)80166-5 . 23827802 . free . 1994FEBSL.340...25A .
  3. Web site: Entrez Gene: LONP1 lon peptidase 1, mitochondrial.
  4. Pinti M, Gibellini L, Liu Y, Xu S, Lu B, Cossarizza A . Mitochondrial Lon protease at the crossroads of oxidative stress, ageing and cancer . Cellular and Molecular Life Sciences . 72 . 24 . 4807–24 . December 2015 . 26363553 . 10.1007/s00018-015-2039-3 . 14668486 . 11113732 .
  5. Lu B, Liu T, Crosby JA, Thomas-Wohlever J, Lee I, Suzuki CK . The ATP-dependent Lon protease of Mus musculus is a DNA-binding protein that is functionally conserved between yeast and mammals . Gene . 306 . 45–55 . March 2003 . 12657466 . 10.1016/s0378-1119(03)00403-7 .
  6. Bezawork-Geleta A, Brodie EJ, Dougan DA, Truscott KN . LON is the master protease that protects against protein aggregation in human mitochondria through direct degradation of misfolded proteins . Scientific Reports . 5 . 1 . 17397 . December 2015 . 26627475 . 4667172 . 10.1038/srep17397 . 2015NatSR...517397B .
  7. Gur E, Sauer RT . Recognition of misfolded proteins by Lon, a AAA(+) protease . Genes & Development . 22 . 16 . 2267–77 . August 2008 . 18708584 . 10.1101/gad.1670908 . 2518814.
  8. Birghan C, Mundt E, Gorbalenya AE . A non-canonical lon proteinase lacking the ATPase domain employs the ser-Lys catalytic dyad to exercise broad control over the life cycle of a double-stranded RNA virus . The EMBO Journal . 19 . 1 . 114–23 . January 2000 . 10619850 . 10.1093/emboj/19.1.114 . 1171783.
  9. Liu T, Lu B, Lee I, Ondrovicová G, Kutejová E, Suzuki CK . DNA and RNA binding by the mitochondrial lon protease is regulated by nucleotide and protein substrate . The Journal of Biological Chemistry . 279 . 14 . 13902–10 . April 2004 . 14739292 . 10.1074/jbc.m309642200 . free .
  10. Lu B, Lee J, Nie X, Li M, Morozov YI, Venkatesh S, Bogenhagen DF, Temiakov D, Suzuki CK . Phosphorylation of human TFAM in mitochondria impairs DNA binding and promotes degradation by the AAA+ Lon protease . Molecular Cell . 49 . 1 . 121–32 . January 2013 . 23201127 . 10.1016/j.molcel.2012.10.023 . 3586414.
  11. Bota DA, Ngo JK, Davies KJ . Downregulation of the human Lon protease impairs mitochondrial structure and function and causes cell death . Free Radical Biology & Medicine . 38 . 5 . 665–77 . March 2005 . 15683722 . 10.1016/j.freeradbiomed.2004.11.017 . 32448357 .
  12. Ngo JK, Pomatto LC, Davies KJ . Upregulation of the mitochondrial Lon Protease allows adaptation to acute oxidative stress but dysregulation is associated with chronic stress, disease, and aging . Redox Biology . 1 . 258–64 . 9 February 2013 . 1 . 24024159 . 10.1016/j.redox.2013.01.015 . 3757690.
  13. Hamon MP, Bulteau AL, Friguet B . Mitochondrial proteases and protein quality control in ageing and longevity . Ageing Research Reviews . 23 . Pt A . 56–66 . September 2015 . 25578288 . 10.1016/j.arr.2014.12.010 . 205667759 .
  14. Dikoglu E, Alfaiz A, Gorna M, Bertola D, Chae JH, Cho TJ, Derbent M, Alanay Y, Guran T, Kim OH, Llerenar JC, Yamamoto G, Superti-Furga G, Reymond A, Xenarios I, Stevenson B, Campos-Xavier B, Bonafé L, Superti-Furga A, Unger S . 6 . Mutations in LONP1, a mitochondrial matrix protease, cause CODAS syndrome . American Journal of Medical Genetics. Part A . 167 . 7 . 1501–9 . July 2015 . 25808063 . 10.1002/ajmg.a.37029 . 24136909 .
  15. Strauss KA, Jinks RN, Puffenberger EG, Venkatesh S, Singh K, Cheng I, Mikita N, Thilagavathi J, Lee J, Sarafianos S, Benkert A, Koehler A, Zhu A, Trovillion V, McGlincy M, Morlet T, Deardorff M, Innes AM, Prasad C, Chudley AE, Lee IN, Suzuki CK . 6 . CODAS syndrome is associated with mutations of LONP1, encoding mitochondrial AAA+ Lon protease . American Journal of Human Genetics . 96 . 1 . 121–35 . January 2015 . 25574826 . 4289676 . 10.1016/j.ajhg.2014.12.003 .
  16. Web site: MIM 600373: Codas Syndrome . OMIM .
  17. Qiao L, Xu L, Yu L, Wynn J, Hernan R, Zhou X, Farkouh-Karoleski C, Krishnan US, Khlevner J, De A, Zygmunt A, Crombleholme T, Lim FY, Needelman H, Cusick RA, Mychaliska GB, Warner BW, Wagner AJ, Danko ME, Chung D, Potoka D, Kosiński P, McCulley DJ, Elfiky M, Azarow K, Fialkowski E, Schindel D, Soffer SZ, Lyon JB, Zalieckas JM, Vardarajan BN, Aspelund G, Duron VP, High FA, Sun X, Donahoe PK, Shen Y, Chung WK . 6 . Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene . American Journal of Human Genetics . 108 . 10 . 1964–1980 . October 2021 . 34547244 . 10.1016/j.ajhg.2021.08.011. 0002-9297 . 8546037 .

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