AP5M1
{{short description|Protein-coding gene in the species Homo sapiens}}
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File:AP5M1 3D Protein Structure.png
AP-5 complex subunit mu (AP5M1), otherwise known as MUDENG (MuD), is a protein that is encoded by the AP5M1 gene.{{Cite journal |last1=Hirst |first1=Jennifer |last2=Barlow |first2=Lael D. |last3=Francisco |first3=Gabriel Casey |last4=Sahlender |first4=Daniela A. |last5=Seaman |first5=Matthew N. J. |last6=Dacks |first6=Joel B. |last7=Robinson |first7=Margaret S. |date=2011-10-11 |title=The fifth adaptor protein complex |journal=PLOS Biology |volume=9 |issue=10 |pages=e1001170 |doi=10.1371/journal.pbio.1001170 |issn=1545-7885 |pmc=3191125 |pmid=22022230 |doi-access=free }} The AP5M1 gene was originally discovered when screening for genes which helped to promote death in Fas-mediated apoptosis.{{Cite journal |last1=Lee |first1=Mi-Rha |last2=Shin |first2=Jin Na |last3=Moon |first3=Ae Ran |last4=Park |first4=Sun-Young |last5=Hong |first5=Gilsun |last6=Lee |first6=Mi-Ja |last7=Yun |first7=Cheol-Won |last8=Seol |first8=Dai-Wu |last9=Piya |first9=Sujan |last10=Bae |first10=Jeehyeon |last11=Oh |first11=Jae-Wook |last12=Kim |first12=Tae-Hyoung |date=2008-06-06 |title=A novel protein, MUDENG, induces cell death in cytotoxic T cells |url=https://pubmed.ncbi.nlm.nih.gov/18395520/ |journal=Biochemical and Biophysical Research Communications |volume=370 |issue=3 |pages=504–508 |doi=10.1016/j.bbrc.2008.03.139 |issn=1090-2104 |pmid=18395520}}{{Cite journal |last1=Choi |first1=J.-H. |last2=Lim |first2=J.-B. |last3=Wickramanayake |first3=D. D. |last4=Wagley |first4=Y. |last5=Kim |first5=J. |last6=Lee |first6=H.-C. |last7=Seo |first7=H. G. |last8=Kim |first8=T.-H. |last9=Oh |first9=J.-W. |date=2016 |title=Characterization of MUDENG, a novel anti-apoptotic protein |journal=Oncogenesis |language=en |volume=5 |issue=5 |pages=e221 |doi=10.1038/oncsis.2016.30 |pmid=27136675 |pmc=4945747 |issn=2157-9024}} It is a highly conserved gene.{{Cite journal |last1=Muthu |first1=Manikandan |last2=Chun |first2=Sechul |last3=Gopal |first3=Judy |last4=Park |first4=Gyun-Seok |last5=Nile |first5=Arti |last6=Shin |first6=Jisoo |last7=Shin |first7=Juhyun |last8=Kim |first8=Tae-Hyoung |last9=Oh |first9=Jae-Wook |date=2020-08-04 |title=The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? |journal=International Journal of Molecular Sciences |volume=21 |issue=15 |pages=5583 |doi=10.3390/ijms21155583 |issn=1422-0067 |pmc=7432215 |pmid=32759789 |doi-access=free }}
MuD is the medium-sized subunit of the AP5 adaptor complex.{{Cite journal |last1=Hirst |first1=Jennifer |last2=Irving |first2=Carol |last3=Borner |first3=Georg H. H. |date=2012-11-21 |title=Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia |journal=Traffic |volume=14 |issue=2 |pages=153–164 |doi=10.1111/tra.12028 |issn=1600-0854 |pmid=23167973 |s2cid=13766991|doi-access=free }} 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).{{Cite journal |last1=Shin |first1=Jin Na |last2=Han |first2=Ji Hye |last3=Kim |first3=Ji-Young |last4=Moon |first4=Ae-Ran |last5=Kim |first5=Ji Eun |last6=Chang |first6=Jeong Hwan |last7=Bae |first7=Jeehyeon |last8=Oh |first8=Jae Wook |last9=Kim |first9=Tae-Hyoung |date=2013-05-31 |title=MUDENG is cleaved by caspase-3 during TRAIL-induced cell death |url=https://pubmed.ncbi.nlm.nih.gov/23665015/ |journal=Biochemical and Biophysical Research Communications |volume=435 |issue=2 |pages=234–238 |doi=10.1016/j.bbrc.2013.04.075 |issn=1090-2104 |pmid=23665015}}{{Cite journal |last1=Won |first1=Miae |last2=Luo |first2=Yongyang |last3=Lee |first3=Dong-Ho |last4=Shin |first4=Eunkyoung |last5=Suh |first5=Dae-Shik |last6=Kim |first6=Tae-Hyoung |last7=Jin |first7=Hanyong |last8=Bae |first8=Jeehyeon |date=2019-10-15 |title=BAX is an essential key mediator of AP5M1-induced apoptosis in cervical carcinoma cells |url=https://pubmed.ncbi.nlm.nih.gov/31427081/ |journal=Biochemical and Biophysical Research Communications |volume=518 |issue=2 |pages=368–373 |doi=10.1016/j.bbrc.2019.08.065 |issn=1090-2104 |pmid=31427081|s2cid=201095590 }}
Structure
MuD consists of 490 amino acids that interact to form a tertiary structure with three domains.{{Cite journal |last1=Muthu |first1=Manikandan |last2=Chun |first2=Sechul |last3=Gopal |first3=Judy |last4=Park |first4=Gyun-Seok |last5=Nile |first5=Arti |last6=Shin |first6=Jisoo |last7=Shin |first7=Juhyun |last8=Kim |first8=Tae-Hyoung |last9=Oh |first9=Jae-Wook |date=2020-08-04 |title=The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? |journal=International Journal of Molecular Sciences |volume=21 |issue=15 |pages=5583 |doi=10.3390/ijms21155583 |issn=1422-0067 |pmc=7432215 |pmid=32759789 |doi-access=free }}{{Cite journal |last1=Choi |first1=J.-H. |last2=Lim |first2=J.-B. |last3=Wickramanayake |first3=D. D. |last4=Wagley |first4=Y. |last5=Kim |first5=J. |last6=Lee |first6=H.-C. |last7=Seo |first7=H. G. |last8=Kim |first8=T.-H. |last9=Oh |first9=J.-W. |date=2016 |title=Characterization of MUDENG, a novel anti-apoptotic protein |journal=Oncogenesis |language=en |volume=5 |issue=5 |pages=e221 |doi=10.1038/oncsis.2016.30 |pmid=27136675 |pmc=4945747 |issn=2157-9024}}
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.{{Cite journal |last1=Lee |first1=Mi-Rha |last2=Shin |first2=Jin Na |last3=Moon |first3=Ae Ran |last4=Park |first4=Sun-Young |last5=Hong |first5=Gilsun |last6=Lee |first6=Mi-Ja |last7=Yun |first7=Cheol-Won |last8=Seol |first8=Dai-Wu |last9=Piya |first9=Sujan |last10=Bae |first10=Jeehyeon |last11=Oh |first11=Jae-Wook |last12=Kim |first12=Tae-Hyoung |date=2008-06-06 |title=A novel protein, MUDENG, induces cell death in cytotoxic T cells |url=https://pubmed.ncbi.nlm.nih.gov/18395520/ |journal=Biochemical and Biophysical Research Communications |volume=370 |issue=3 |pages=504–508 |doi=10.1016/j.bbrc.2008.03.139 |issn=1090-2104 |pmid=18395520}}{{Cite journal |last1=Shin |first1=Jin Na |last2=Han |first2=Ji Hye |last3=Kim |first3=Ji-Young |last4=Moon |first4=Ae-Ran |last5=Kim |first5=Ji Eun |last6=Chang |first6=Jeong Hwan |last7=Bae |first7=Jeehyeon |last8=Oh |first8=Jae Wook |last9=Kim |first9=Tae-Hyoung |date=2013-05-31 |title=MUDENG is cleaved by caspase-3 during TRAIL-induced cell death |url=https://pubmed.ncbi.nlm.nih.gov/23665015/ |journal=Biochemical and Biophysical Research Communications |volume=435 |issue=2 |pages=234–238 |doi=10.1016/j.bbrc.2013.04.075 |issn=1090-2104 |pmid=23665015}}
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.{{Cite journal |last1=Won |first1=Miae |last2=Luo |first2=Yongyang |last3=Lee |first3=Dong-Ho |last4=Shin |first4=Eunkyoung |last5=Suh |first5=Dae-Shik |last6=Kim |first6=Tae-Hyoung |last7=Jin |first7=Hanyong |last8=Bae |first8=Jeehyeon |date=2019-10-15 |title=BAX is an essential key mediator of AP5M1-induced apoptosis in cervical carcinoma cells |url=https://pubmed.ncbi.nlm.nih.gov/31427081/ |journal=Biochemical and Biophysical Research Communications |volume=518 |issue=2 |pages=368–373 |doi=10.1016/j.bbrc.2019.08.065 |issn=1090-2104 |pmid=31427081|s2cid=201095590 }} It is known, however, that MuD regulates the expression of BAX, a pro-apoptotic member of the Bcl-2 family of proteins.{{Cite journal |last1=Muthu |first1=Manikandan |last2=Chun |first2=Sechul |last3=Gopal |first3=Judy |last4=Park |first4=Gyun-Seok |last5=Nile |first5=Arti |last6=Shin |first6=Jisoo |last7=Shin |first7=Juhyun |last8=Kim |first8=Tae-Hyoung |last9=Oh |first9=Jae-Wook |date=2020-08-04 |title=The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? |journal=International Journal of Molecular Sciences |volume=21 |issue=15 |pages=5583 |doi=10.3390/ijms21155583 |issn=1422-0067 |pmc=7432215 |pmid=32759789 |doi-access=free }} Due to— and dependent upon— this relationship, MuD has been able to induce cell death in tumor cells.{{Cite journal |last1=Lee |first1=Mi-Rha |last2=Shin |first2=Jin Na |last3=Moon |first3=Ae Ran |last4=Park |first4=Sun-Young |last5=Hong |first5=Gilsun |last6=Lee |first6=Mi-Ja |last7=Yun |first7=Cheol-Won |last8=Seol |first8=Dai-Wu |last9=Piya |first9=Sujan |last10=Bae |first10=Jeehyeon |last11=Oh |first11=Jae-Wook |last12=Kim |first12=Tae-Hyoung |date=2008-06-06 |title=A novel protein, MUDENG, induces cell death in cytotoxic T cells |url=https://pubmed.ncbi.nlm.nih.gov/18395520/ |journal=Biochemical and Biophysical Research Communications |volume=370 |issue=3 |pages=504–508 |doi=10.1016/j.bbrc.2008.03.139 |issn=1090-2104 |pmid=18395520}}
Additionally, MuD has been suggested to be involved in endosomal trafficking.{{Cite journal |last1=Hirst |first1=Jennifer |last2=Irving |first2=Carol |last3=Borner |first3=Georg H. H. |date=2012-11-21 |title=Adaptor protein complexes AP-4 and AP-5: new players in endosomal trafficking and progressive spastic paraplegia |journal=Traffic |volume=14 |issue=2 |pages=153–164 |doi=10.1111/tra.12028 |issn=1600-0854 |pmid=23167973 |s2cid=13766991|doi-access=free }}
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.{{Cite journal |last1=Choi |first1=J.-H. |last2=Lim |first2=J.-B. |last3=Wickramanayake |first3=D. D. |last4=Wagley |first4=Y. |last5=Kim |first5=J. |last6=Lee |first6=H.-C. |last7=Seo |first7=H. G. |last8=Kim |first8=T.-H. |last9=Oh |first9=J.-W. |date=2016 |title=Characterization of MUDENG, a novel anti-apoptotic protein |journal=Oncogenesis |language=en |volume=5 |issue=5 |pages=e221 |doi=10.1038/oncsis.2016.30 |pmid=27136675 |pmc=4945747 |issn=2157-9024}}{{Cite journal |last1=Muthu |first1=Manikandan |last2=Chun |first2=Sechul |last3=Gopal |first3=Judy |last4=Park |first4=Gyun-Seok |last5=Nile |first5=Arti |last6=Shin |first6=Jisoo |last7=Shin |first7=Juhyun |last8=Kim |first8=Tae-Hyoung |last9=Oh |first9=Jae-Wook |date=2020-08-04 |title=The MUDENG Augmentation: A Genesis in Anti-Cancer Therapy? |journal=International Journal of Molecular Sciences |volume=21 |issue=15 |pages=5583 |doi=10.3390/ijms21155583 |issn=1422-0067 |pmc=7432215 |pmid=32759789 |doi-access=free }}{{Cite journal |last1=Shin |first1=Jin Na |last2=Han |first2=Ji Hye |last3=Kim |first3=Ji-Young |last4=Moon |first4=Ae-Ran |last5=Kim |first5=Ji Eun |last6=Chang |first6=Jeong Hwan |last7=Bae |first7=Jeehyeon |last8=Oh |first8=Jae Wook |last9=Kim |first9=Tae-Hyoung |date=2013-05-31 |title=MUDENG is cleaved by caspase-3 during TRAIL-induced cell death |url=https://pubmed.ncbi.nlm.nih.gov/23665015/ |journal=Biochemical and Biophysical Research Communications |volume=435 |issue=2 |pages=234–238 |doi=10.1016/j.bbrc.2013.04.075 |issn=1090-2104 |pmid=23665015}}{{Cite journal |last1=Dimberg |first1=L. Y. |last2=Anderson |first2=C. K. |last3=Camidge |first3=R. |last4=Behbakht |first4=K. |last5=Thorburn |first5=A. |last6=Ford |first6=H. L. |date=2013-03-14 |title=On the TRAIL to successful cancer therapy? Predicting and counteracting resistance against TRAIL-based therapeutics |journal=Oncogene |volume=32 |issue=11 |pages=1341–1350 |doi=10.1038/onc.2012.164 |issn=1476-5594 |pmc=4502956 |pmid=22580613}} 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.