AP5M1 explained

AP-5 complex subunit mu (AP5M1), otherwise known as MUDENG (MuD), is a protein that is encoded by the AP5M1 gene.[1] The AP5M1 gene was originally discovered when screening for genes which helped to promote death in Fas-mediated apoptosis.[2] [3] It is a highly conserved gene.[4]

MuD is the medium-sized subunit of the AP5 adaptor complex.[5] MuD is expressed throughout the body and is located within both the mitochondria as well as the endoplasmic reticulum (ER) of cells.

MuD has been shown to have the ability to induce apoptosis; however, there is evidence that it plays an anti-apoptotic role in apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).[6] [7]

Structure

MuD consists of 490 amino acids that interact to form a tertiary structure with three domains.[8] [9]

The overall structure shares similarities with adaptor protein (AP) complexes that are related to clathrin-mediated endocytosis; amino acids 197 through 417 are a shared adaptin domain found in AP μ subunits.[10] [11]

Within the adaptin domain are two aspartic acids, D276 and D290, which serve as binding sites for caspase-3.

Function

The overall function of MuD remains unclear.[12] It is known, however, that MuD regulates the expression of BAX, a pro-apoptotic member of the Bcl-2 family of proteins.[13] Due to— and dependent upon— this relationship, MuD has been able to induce cell death in tumor cells.[14]

Additionally, MuD has been suggested to be involved in endosomal trafficking.[15]

TRAIL and MuD

TRAIL, an apoptosis-inducing ligand, activates caspase-8 and caspase-3, which initiate the intrinsic pathway of apoptosis by cleaving BH3 interacting-domain death agonist (Bid) into tBid, another pro-apoptotic member of the Bl-2 protein family.[16] [17] [18] [19] MuD interferes with this process because D276 and D290 act as alternative binding sites for caspase-3, decreasing the amount of Bid that gets cleaved. Tumor cells being treated with TRAIL are 32% more likely to survive when MuD is being expressed.   

References

  1. Hirst . Jennifer . Barlow . Lael D. . Francisco . Gabriel Casey . Sahlender . Daniela A. . Seaman . Matthew N. J. . Dacks . Joel B. . Robinson . Margaret S. . 2011-10-11 . The fifth adaptor protein complex . PLOS Biology . 9 . 10 . e1001170 . 10.1371/journal.pbio.1001170 . 1545-7885 . 3191125 . 22022230 . free .
  2. Lee . Mi-Rha . Shin . Jin Na . Moon . Ae Ran . Park . Sun-Young . Hong . Gilsun . Lee . Mi-Ja . Yun . Cheol-Won . Seol . Dai-Wu . Piya . Sujan . Bae . Jeehyeon . Oh . Jae-Wook . Kim . Tae-Hyoung . 2008-06-06 . A novel protein, MUDENG, induces cell death in cytotoxic T cells . Biochemical and Biophysical Research Communications . 370 . 3 . 504–508 . 10.1016/j.bbrc.2008.03.139 . 1090-2104 . 18395520.
  3. Choi . J.-H. . Lim . J.-B. . Wickramanayake . D. D. . Wagley . Y. . Kim . J. . Lee . H.-C. . Seo . H. G. . Kim . T.-H. . Oh . J.-W. . 2016 . Characterization of MUDENG, a novel anti-apoptotic protein . Oncogenesis . en . 5 . 5 . e221 . 10.1038/oncsis.2016.30 . 27136675 . 4945747 . 2157-9024.
  4. Muthu . Manikandan . Chun . Sechul . Gopal . Judy . Park . Gyun-Seok . Nile . Arti . Shin . Jisoo . Shin . Juhyun . Kim . Tae-Hyoung . Oh . Jae-Wook . 2020-08-04 . The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? . International Journal of Molecular Sciences . 21 . 15 . 5583 . 10.3390/ijms21155583 . 1422-0067 . 7432215 . 32759789 . free .
  5. Hirst . Jennifer . Irving . Carol . Borner . Georg H. H. . 2012-11-21 . Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia . Traffic . 14 . 2 . 153–164 . 10.1111/tra.12028 . 1600-0854 . 23167973 . 13766991. free .
  6. Shin . Jin Na . Han . Ji Hye . Kim . Ji-Young . Moon . Ae-Ran . Kim . Ji Eun . Chang . Jeong Hwan . Bae . Jeehyeon . Oh . Jae Wook . Kim . Tae-Hyoung . 2013-05-31 . MUDENG is cleaved by caspase-3 during TRAIL-induced cell death . Biochemical and Biophysical Research Communications . 435 . 2 . 234–238 . 10.1016/j.bbrc.2013.04.075 . 1090-2104 . 23665015.
  7. Won . Miae . Luo . Yongyang . Lee . Dong-Ho . Shin . Eunkyoung . Suh . Dae-Shik . Kim . Tae-Hyoung . Jin . Hanyong . Bae . Jeehyeon . 2019-10-15 . BAX is an essential key mediator of AP5M1-induced apoptosis in cervical carcinoma cells . Biochemical and Biophysical Research Communications . 518 . 2 . 368–373 . 10.1016/j.bbrc.2019.08.065 . 1090-2104 . 31427081. 201095590 .
  8. Muthu . Manikandan . Chun . Sechul . Gopal . Judy . Park . Gyun-Seok . Nile . Arti . Shin . Jisoo . Shin . Juhyun . Kim . Tae-Hyoung . Oh . Jae-Wook . 2020-08-04 . The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? . International Journal of Molecular Sciences . 21 . 15 . 5583 . 10.3390/ijms21155583 . 1422-0067 . 7432215 . 32759789 . free .
  9. Choi . J.-H. . Lim . J.-B. . Wickramanayake . D. D. . Wagley . Y. . Kim . J. . Lee . H.-C. . Seo . H. G. . Kim . T.-H. . Oh . J.-W. . 2016 . Characterization of MUDENG, a novel anti-apoptotic protein . Oncogenesis . en . 5 . 5 . e221 . 10.1038/oncsis.2016.30 . 27136675 . 4945747 . 2157-9024.
  10. Lee . Mi-Rha . Shin . Jin Na . Moon . Ae Ran . Park . Sun-Young . Hong . Gilsun . Lee . Mi-Ja . Yun . Cheol-Won . Seol . Dai-Wu . Piya . Sujan . Bae . Jeehyeon . Oh . Jae-Wook . Kim . Tae-Hyoung . 2008-06-06 . A novel protein, MUDENG, induces cell death in cytotoxic T cells . Biochemical and Biophysical Research Communications . 370 . 3 . 504–508 . 10.1016/j.bbrc.2008.03.139 . 1090-2104 . 18395520.
  11. Shin . Jin Na . Han . Ji Hye . Kim . Ji-Young . Moon . Ae-Ran . Kim . Ji Eun . Chang . Jeong Hwan . Bae . Jeehyeon . Oh . Jae Wook . Kim . Tae-Hyoung . 2013-05-31 . MUDENG is cleaved by caspase-3 during TRAIL-induced cell death . Biochemical and Biophysical Research Communications . 435 . 2 . 234–238 . 10.1016/j.bbrc.2013.04.075 . 1090-2104 . 23665015.
  12. Won . Miae . Luo . Yongyang . Lee . Dong-Ho . Shin . Eunkyoung . Suh . Dae-Shik . Kim . Tae-Hyoung . Jin . Hanyong . Bae . Jeehyeon . 2019-10-15 . BAX is an essential key mediator of AP5M1-induced apoptosis in cervical carcinoma cells . Biochemical and Biophysical Research Communications . 518 . 2 . 368–373 . 10.1016/j.bbrc.2019.08.065 . 1090-2104 . 31427081. 201095590 .
  13. Muthu . Manikandan . Chun . Sechul . Gopal . Judy . Park . Gyun-Seok . Nile . Arti . Shin . Jisoo . Shin . Juhyun . Kim . Tae-Hyoung . Oh . Jae-Wook . 2020-08-04 . The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? . International Journal of Molecular Sciences . 21 . 15 . 5583 . 10.3390/ijms21155583 . 1422-0067 . 7432215 . 32759789 . free .
  14. Lee . Mi-Rha . Shin . Jin Na . Moon . Ae Ran . Park . Sun-Young . Hong . Gilsun . Lee . Mi-Ja . Yun . Cheol-Won . Seol . Dai-Wu . Piya . Sujan . Bae . Jeehyeon . Oh . Jae-Wook . Kim . Tae-Hyoung . 2008-06-06 . A novel protein, MUDENG, induces cell death in cytotoxic T cells . Biochemical and Biophysical Research Communications . 370 . 3 . 504–508 . 10.1016/j.bbrc.2008.03.139 . 1090-2104 . 18395520.
  15. Hirst . Jennifer . Irving . Carol . Borner . Georg H. H. . 2012-11-21 . Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia . Traffic . 14 . 2 . 153–164 . 10.1111/tra.12028 . 1600-0854 . 23167973 . 13766991. free .
  16. Choi . J.-H. . Lim . J.-B. . Wickramanayake . D. D. . Wagley . Y. . Kim . J. . Lee . H.-C. . Seo . H. G. . Kim . T.-H. . Oh . J.-W. . 2016 . Characterization of MUDENG, a novel anti-apoptotic protein . Oncogenesis . en . 5 . 5 . e221 . 10.1038/oncsis.2016.30 . 27136675 . 4945747 . 2157-9024.
  17. Muthu . Manikandan . Chun . Sechul . Gopal . Judy . Park . Gyun-Seok . Nile . Arti . Shin . Jisoo . Shin . Juhyun . Kim . Tae-Hyoung . Oh . Jae-Wook . 2020-08-04 . The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? . International Journal of Molecular Sciences . 21 . 15 . 5583 . 10.3390/ijms21155583 . 1422-0067 . 7432215 . 32759789 . free .
  18. Shin . Jin Na . Han . Ji Hye . Kim . Ji-Young . Moon . Ae-Ran . Kim . Ji Eun . Chang . Jeong Hwan . Bae . Jeehyeon . Oh . Jae Wook . Kim . Tae-Hyoung . 2013-05-31 . MUDENG is cleaved by caspase-3 during TRAIL-induced cell death . Biochemical and Biophysical Research Communications . 435 . 2 . 234–238 . 10.1016/j.bbrc.2013.04.075 . 1090-2104 . 23665015.
  19. Dimberg . L. Y. . Anderson . C. K. . Camidge . R. . Behbakht . K. . Thorburn . A. . Ford . H. L. . 2013-03-14 . On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics . Oncogene . 32 . 11 . 1341–1350 . 10.1038/onc.2012.164 . 1476-5594 . 4502956 . 22580613.

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