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Current Protein & Peptide Science


ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

Review Article

Structural Analysis of the Interaction between Bcl-xL and the Noncanonical BH3 Domain of Non-Bcl-2 Family Proteins

Author(s): Bonsu Ku*

Volume 24, Issue 4, 2023

Published on: 07 April, 2023

Page: [296 - 306] Pages: 11

DOI: 10.2174/1389203724666230314164040

Price: $65


Anti-apoptotic and anti-autophagic Bcl-2 homologues commonly contain a hydrophobic groove in which the BH3 domain is accommodated. The BH3 domain is usually considered a feature of Bcl-2 family members; however, it has also been found in various non-Bcl-2 family proteins. Although interactions among Bcl-2 family members have been extensively investigated and highlighted, those mediated by the BH3 domain of non-Bcl-2 family proteins have not been the focus of substantial research. In this review, the author conducted a structural analysis of Bcl-xL complexed with the BH3 domain of four non-Bcl-2 family proteins, Beclin 1, SOUL, TCTP, and Pxt1, at an atomic level. Although the overall Bcl-xL-binding modes are similar among these proteins, they are characterized by limited sequence conservation of the BH3 consensus motif and differences in residues involved in complex formation. Based on the structural analysis, the author suggests that more “undiscovered” BH3 domain-containing proteins might exist, which have been unidentified due to their limited sequence conservation but can bind to Bcl-2 family proteins and control apoptosis, autophagy, or other biological processes.

Keywords: Bcl-2, Bcl-xL, BH3, non-Bcl-2 family proteins, Beclin 1, SOUL, TCTP, Pxt1.

Graphical Abstract
Singh, R.; Letai, A.; Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol., 2019, 20(3), 175-193.
[] [PMID: 30655609]
Czabotar, P.E.; Lessene, G.; Strasser, A.; Adams, J.M. Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy. Nat. Rev. Mol. Cell Biol., 2014, 15(1), 49-63.
[] [PMID: 24355989]
Chong, S.J.F.; Marchi, S.; Petroni, G.; Kroemer, G.; Galluzzi, L.; Pervaiz, S. Noncanonical cell fate regulation by BCL-2 proteins. Trends Cell Biol., 2020, 30(7), 537-555.
[] [PMID: 32307222]
Gross, A.; Katz, S.G. Non-apoptotic functions of BCL-2 family proteins. Cell Death Differ., 2017, 24(8), 1348-1358.
[] [PMID: 28234359]
Zheng, C.; Liu, T.; Liu, H.; Wang, J. Role of BCL-2 family proteins in apoptosis and its regulation by nutrients. Curr. Protein Pept. Sci., 2020, 21(8), 799-806.
[] [PMID: 31880257]
Banjara, S.; Suraweera, C.D.; Hinds, M.G.; Kvansakul, M. The BCL-2 family: ancient origins, conserved structures, and divergent mechanisms. Biomolecules, 2020, 10(1), 128.
[] [PMID: 31940915]
Ku, B.; Liang, C.; Jung, J.U.; Oh, B.H. Evidence that inhibition of BAX activation by BCL-2 involves its tight and preferential interaction with the BH3 domain of BAX. Cell Res., 2011, 21(4), 627-641.
[] [PMID: 21060336]
Sinha, S.; Levine, B. The autophagy effector Beclin 1: a novel BH3-only protein. Oncogene, 2008, 27(S1)(Suppl. 1), S137-S148.
[] [PMID: 19641499]
Szigeti, A.; Hocsak, E.; Rapolti, E.; Racz, B.; Boronkai, A.; Pozsgai, E.; Debreceni, B.; Bognar, Z.; Bellyei, S.; Sumegi, B.; Gallyas, F., Jr Facilitation of mitochondrial outer and inner membrane permeabilization and cell death in oxidative stress by a novel BCL-2 homology 3 domain protein. J. Biol. Chem., 2010, 285(3), 2140-2151.
[] [PMID: 19901022]
Thébault, S.; Agez, M.; Chi, X.; Stojko, J.; Cura, V.; Telerman, S.B.; Maillet, L.; Gautier, F.; Billas-Massobrio, I.; Birck, C.; Troffer-Charlier, N.; Karafin, T.; Honoré, J.; Senff-Ribeiro, A.; Montessuit, S.; Johnson, C.M.; Juin, P.; Cianférani, S.; Martinou, J.C.; Andrews, D.W.; Amson, R.; Telerman, A.; Cavarelli, J. TCTP contains a BH3-like domain, which instead of inhibiting, activates BCL-xL. Sci. Rep., 2016, 6(1), 19725.
[] [PMID: 26813996]
Kaczmarek, K.; Studencka, M.; Meinhardt, A.; Wieczerzak, K.; Thoms, S.; Engel, W.; Grzmil, P. Overexpression of peroxisomal testis-specific 1 protein induces germ cell apoptosis and leads to infertility in male mice. Mol. Biol. Cell, 2011, 22(10), 1766-1779.
[] [PMID: 21460186]
Kvansakul, M.; Hinds, M.G. Structural biology of the BCL-2 family and its mimicry by viral proteins. Cell Death Dis., 2013, 4(11), e909.
[] [PMID: 24201808]
Lee, E.F.; Fairlie, W.D. The structural biology of BCL-xL. Int. J. Mol. Sci., 2019, 20(9), 2234.
[] [PMID: 31067648]
Kvansakul, M.; Hinds, M.G. The BCL-2 family: structures, interactions and targets for drug discovery. Apoptosis, 2015, 20(2), 136-150.
Petros, A.M.; Olejniczak, E.T.; Fesik, S.W. Structural biology of the BCL-2 family of proteins. Biochim. Biophys. Acta Mol. Cell Res., 2004, 1644(2-3), 83-94.
[] [PMID: 14996493]
Sivakumar, D.; Sivaraman, T. A review on structures and functions of BCL-2 family proteins from Homo sapiens. Protein Pept. Lett., 2016, 23(10), 932-941.
[] [PMID: 27449944]
Muchmore, S.W.; Sattler, M.; Liang, H.; Meadows, R.P.; Harlan, J.E.; Yoon, H.S.; Nettesheim, D.; Chang, B.S.; Thompson, C.B.; Wong, S.L.; Ng, S.C.; Fesik, S.W. X-ray and NMR structure of human BCL-xL, an inhibitor of programmed cell death. Nature, 1996, 381(6580), 335-341.
[] [PMID: 8692274]
Sattler, M.; Liang, H.; Nettesheim, D.; Meadows, R.P.; Harlan, J.E.; Eberstadt, M.; Yoon, H.S.; Shuker, S.B.; Chang, B.S.; Minn, A.J.; Thompson, C.B.; Fesik, S.W. Structure of BCL-xL-Bak peptide complex: recognition between regulators of apoptosis. Science, 1997, 275(5302), 983-986.
[] [PMID: 9020082]
Czabotar, P.E.; Lee, E.F.; Thompson, G.V.; Wardak, A.Z.; Fairlie, W.D.; Colman, P.M. Mutation to Bax beyond the BH3 domain disrupts interactions with pro-survival proteins and promotes apoptosis. J. Biol. Chem., 2011, 286(9), 7123-7131.
[] [PMID: 21199865]
Liu, X.; Dai, S.; Zhu, Y.; Marrack, P.; Kappler, J.W. The structure of a BCL-xL/Bim fragment complex: Implications for Bim function. Immunity, 2003, 19(3), 341-352.
[] [PMID: 14499110]
Kim, J-S.; Ku, B.; Woo, T-G.; Oh, A-Y.; Jung, Y-S.; Soh, Y-M.; Yeom, J-H.; Lee, K.; Park, B-J.; Oh, B-H.; Ha, N-C. Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain. Cell Death Dis., 2015, 6(7), e1804.
[] [PMID: 26136077]
Follis, A.V.; Chipuk, J.E.; Fisher, J.C.; Yun, M.K.; Grace, C.R.; Nourse, A.; Baran, K.; Ou, L.; Min, L.; White, S.W.; Green, D.R.; Kriwacki, R.W. PUMA binding induces partial unfolding within BCL-xL to disrupt p53 binding and promote apoptosis. Nat. Chem. Biol., 2013, 9(3), 163-168.
[] [PMID: 23340338]
Petros, A.M.; Nettesheim, D.G.; Wang, Y.; Olejniczak, E.T.; Meadows, R.P.; Mack, J.; Swift, K.; Matayoshi, E.D.; Zhang, H.; Fesik, S.W.; Thompson, C.B. Rationale for BCL-XL/Bad peptide complex formation from structure, mutagenesis, and biophysical studies. Protein Sci., 2000, 9(12), 2528-2534.
[] [PMID: 11206074]
Ku, B. Woo, J.S.; Liang, C.; Lee, K.H.; Hong, H.S.; e, X.; Kim, K.S.; Jung, J.U.; Oh, B.H. Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine γ-herpesvirus 68. PLoS Pathog., 2008, 4(2), e25.
[] [PMID: 18248095]
Tran, S.; Fairlie, W.D.; Lee, E.F. BECLIN1: Protein structure, function and regulation. Cells, 2021, 10(6), 1522.
[] [PMID: 34204202]
Ryter, S.W.; Cloonan, S.M.; Choi, A.M.K. Autophagy: A critical regulator of cellular metabolism and homeostasis. Mol. Cells, 2013, 36(1), 7-16.
[] [PMID: 23708729]
Xu, H.D.; Qin, Z.H. Beclin 1, BCL-2 and autophagy. Adv. Exp. Med. Biol., 2019, 1206, 109-126.
[] [PMID: 31776982]
Rostislavleva, K.; Soler, N.; Ohashi, Y.; Zhang, L.; Pardon, E.; Burke, J.E.; Masson, G.R.; Johnson, C.; Steyaert, J.; Ktistakis, N.T.; Williams, R.L. Structure and flexibility of the endosomal Vps34 complex reveals the basis of its function on membranes. Science, 2015, 350(6257), aac7365.
[] [PMID: 26450213]
Levine, B.; Sinha, S.C.; Kroemer, G. BCL-2 family members: Dual regulators of apoptosis and autophagy. Autophagy, 2008, 4(5), 600-606.
[] [PMID: 18497563]
Liang, C. e, X.; Jung, J.U.Downregulation of autophagy by herpesvirus Bcl-2 homologs. Autophagy, 2008, 4(3), 268-272.
[] [PMID: 17993780]
Ku, B.; Woo, J.S.; Liang, C.; Lee, K.H.; Jung, J.U.; Oh, B.H. An insight into the mechanistic role of Beclin 1 and its inhibition by prosurvival BCL-2 family proteins. Autophagy, 2008, 4(4), 519-520.
[] [PMID: 18334862]
Mei, Y.; Su, M.; Sanishvili, R.; Chakravarthy, S.; Colbert, C.L.; Sinha, S.C. Identification of BECN1 and ATG14 coiled-coil interface residues that are important for starvation-induced autophagy. Biochemistry, 2016, 55(30), 4239-4253.
[] [PMID: 27383850]
Wu, S.; He, Y.; Qiu, X.; Yang, W.; Liu, W.; Li, X.; Li, Y.; Shen, H.M.; Wang, R.; Yue, Z.; Zhao, Y. Targeting the potent Beclin 1-UVRAG coiled-coil interaction with designed peptides enhances autophagy and endolysosomal trafficking. Proc. Natl. Acad. Sci. USA, 2018, 115(25), E5669-E5678.
[] [PMID: 29866835]
Li, X.; He, L.; Che, K.H.; Funderburk, S.F.; Pan, L.; Pan, N.; Zhang, M.; Yue, Z.; Zhao, Y. Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat. Commun., 2012, 3(1), 662.
[] [PMID: 22314358]
Huang, W.; Choi, W.; Hu, W.; Mi, N.; Guo, Q.; Ma, M.; Liu, M.; Tian, Y.; Lu, P.; Wang, F.L.; Deng, H.; Liu, L.; Gao, N.; Yu, L.; Shi, Y. Crystal structure and biochemical analyses reveal Beclin 1 as a novel membrane binding protein. Cell Res., 2012, 22(3), 473-489.
[] [PMID: 22310240]
Pattingre, S.; Tassa, A.; Qu, X.; Garuti, R.; Liang, X.H.; Mizushima, N.; Packer, M.; Schneider, M.D.; Levine, B. BCL-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell, 2005, 122(6), 927-939.
[] [PMID: 16179260]
Oberstein, A.; Jeffrey, P.D.; Shi, Y. Crystal structure of the BCL-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J. Biol. Chem., 2007, 282(17), 13123-13132.
[] [PMID: 17337444]
Feng, W.; Huang, S.; Wu, H.; Zhang, M. Molecular basis of BCL-xL’s target recognition versatility revealed by the structure of BCL-xL in complex with the BH3 domain of Beclin-1. J. Mol. Biol., 2007, 372(1), 223-235.
[] [PMID: 17659302]
Sinha, S.C.; Colbert, C.L.; Becker, N.; Wei, Y.; Levine, B. Molecular basis of the regulation of Beclin 1-dependent autophagy by the γ-herpesvirus 68 BCL-2 homolog M11. Autophagy, 2008, 4(8), 989-997.
[] [PMID: 18797192]
Lee, E.F.; Smith, N.A.; Soares da Costa, T.P.; Meftahi, N.; Yao, S.; Harris, T.J.; Tran, S.; Pettikiriarachchi, A.; Perugini, M.A.; Keizer, D.W.; Evangelista, M.; Smith, B.J.; Fairlie, W.D. Structural insights into BCL2 pro-survival protein interactions with the key autophagy regulator BECN1 following phosphorylation by STK4/MST1. Autophagy, 2019, 15(5), 785-795.
[] [PMID: 30626284]
Su, M.; Mei, Y.; Sanishvili, R.; Levine, B.; Colbert, C.L.; Sinha, S. Targeting γ-herpesvirus 68 BCL-2-mediated down-regulation of autophagy. J. Biol. Chem., 2014, 289(12), 8029-8040.
[] [PMID: 24443581]
Zalckvar, E.; Berissi, H.; Mizrachy, L.; Idelchuk, Y.; Koren, I.; Eisenstein, M.; Sabanay, H.; Pinkas-Kramarski, R.; Kimchi, A. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from BCL-XL and induction of autophagy. EMBO Rep., 2009, 10(3), 285-292.
[] [PMID: 19180116]
Gurkar, A.U.; Chu, K.; Raj, L.; Bouley, R.; Lee, S.H.; Kim, Y.B.; Dunn, S.E.; Mandinova, A.; Lee, S.W. Identification of ROCK1 kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress. Nat. Commun., 2013, 4(1), 2189.
[] [PMID: 23877263]
Maejima, Y.; Kyoi, S.; Zhai, P.; Liu, T.; Li, H.; Ivessa, A.; Sciarretta, S.; Del Re, D.P.; Zablocki, D.K.; Hsu, C.P.; Lim, D.S.; Isobe, M.; Sadoshima, J. Mst1 inhibits autophagy by promoting the interaction between Beclin1 and BCL-2. Nat. Med., 2013, 19(11), 1478-1488.
[] [PMID: 24141421]
Szigeti, A.; Bellyei, S.; Gasz, B.; Boronkai, A.; Hocsak, E.; Minik, O.; Bognar, Z.; Varbiro, G.; Sumegi, B.; Gallyas, F., Jr Induction of necrotic cell death and mitochondrial permeabilization by heme binding protein 2/SOUL. FEBS Lett., 2006, 580(27), 6447-6454.
[] [PMID: 17098234]
Zylka, M.J.; Reppert, S.M. Discovery of a putative heme-binding protein family (SOUL/HBP) by two-tissue suppression subtractive hybridization and database searches. Brain Res. Mol. Brain Res., 1999, 74(1-2), 175-181.
[] [PMID: 10640688]
Ambrosi, E.; Capaldi, S.; Bovi, M.; Saccomani, G.; Perduca, M.; Monaco, H.L. Structural changes in the BH3 domain of SOUL protein upon interaction with the anti-apoptotic protein BCL-xL. Biochem. J., 2011, 438(2), 291-301.
[] [PMID: 21639858]
Chen, L.; Willis, S.N.; Wei, A.; Smith, B.J.; Fletcher, J.I.; Hinds, M.G.; Colman, P.M.; Day, C.L.; Adams, J.M.; Huang, D.C.S. Differential targeting of prosurvival BCL-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol. Cell, 2005, 17(3), 393-403.
[] [PMID: 15694340]
Bommer, U.A.; Thiele, B.J. The translationally controlled tumour protein (TCTP). Int. J. Biochem. Cell Biol., 2004, 36(3), 379-385.
[] [PMID: 14687915]
Seo, E.J.; Fischer, N.; Efferth, T. Role of TCTP for cellular differentiation and cancer therapy. Results Probl. Cell Differ., 2017, 64, 263-281.
[] [PMID: 29149414]
Bommer, U.A. The translational controlled tumour protein TCTP: biological functions and regulation. Results Probl. Cell Differ., 2017, 64, 69-126.
[] [PMID: 29149404]
Liu, H.; Peng, H.W.; Cheng, Y.S.; Yuan, H.S.; Yang-Yen, H.F. Stabilization and enhancement of the antiapoptotic activity of mcl-1 by TCTP. Mol. Cell. Biol., 2005, 25(8), 3117-3126.
[] [PMID: 15798198]
Susini, L.; Besse, S.; Duflaut, D.; Lespagnol, A.; Beekman, C.; Fiucci, G.; Atkinson, A.R.; Busso, D.; Poussin, P.; Marine, J-C.; Martinou, J-C.; Cavarelli, J.; Moras, D.; Amson, R.; Telerman, A. TCTP protects from apoptotic cell death by antagonizing bax function. Cell Death Differ., 2008, 15(8), 1211-1220.
[] [PMID: 18274553]
Grzmil, P.; Burfeind, C.; Preuss, T.; Dixkens, C.; Wolf, S.; Engel, W.; Burfeind, P. The putative peroxisomal gene <i>Pxt1</i> is exclusively expressed in the testis. Cytogenet. Genome Res., 2007, 119(1-2), 74-82.
[] [PMID: 18160785]
Lim, D.; Jin, S.; Shin, H.C.; Kim, W.; Choi, J.S.; Oh, D.B.; Kim, S.J.; Seo, J.; Ku, B. Structural and biochemical analyses of BCL-xL in complex with the BH3 domain of peroxisomal testis-specific 1. Biochem. Biophys. Res. Commun., 2022, 625, 174-180.
[] [PMID: 35964379]

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