8j4i

Structural highlights

Function

PHB2_HUMAN Protein with pleiotropic attributes mediated in a cell-compartment- and tissue-specific manner, which include the plasma membrane-associated cell signaling functions, mitochondrial chaperone, and transcriptional co-regulator of transcription factors and sex steroid hormones in the nucleus.^{[1] [2] [3] [4] [5] [6]} In the mitochondria, together with PHB, forms large ring complexes (prohibitin complexes) in the inner mitochondrial membrane (IMM) and functions as a chaperone protein that stabilizes mitochondrial respiratory enzymes and maintains mitochondrial integrity in the IMM, which is required for mitochondrial morphogenesis, neuronal survival, and normal lifespan (Probable). The prohibitin complex, with DNAJC19, regulates cardiolipin remodeling and the protein turnover of OMA1 in a cardiolipin-binding manner (By similarity). Also regulates cytochrome-c oxidase assembly (COX) and mitochondrial respiration (PubMed:11302691, PubMed:20959514). Binding to sphingoid 1-phosphate (SPP) modulates its regulator activity (PubMed:11302691, PubMed:20959514). Has a key role of mitophagy receptor involved in targeting mitochondria for autophagic degradation (PubMed:28017329). Involved in mitochondrial-mediated antiviral innate immunity, activates RIG-I-mediated signal transduction and production of IFNB1 and pro-inflammatory cytokine IL6 (PubMed:31522117).[UniProtKB:O35129]^{[7] [8] [9] [10] [11]} In the nucleus, serves as transcriptional co-regulator (Probable). Acts as a mediator of transcriptional repression by nuclear hormone receptors via recruitment of histone deacetylases. Functions as an estrogen receptor (ER)-selective coregulator that potentiates the inhibitory activities of antiestrogens and represses the activity of estrogens. Competes with NCOA1 for modulation of ER transcriptional activity (By similarity).[UniProtKB:O35129]^[12] In the plasma membrane, is involved in IGFBP6-induced cell migration (PubMed:24003225). Cooperates with CD86 to mediate CD86-signaling in B lymphocytes that regulates the level of IgG1 produced through the activation of distal signaling intermediates. Upon CD40 engagement, required to activate NF-kappa-B signaling pathway via phospholipase C and protein kinase C activation (By similarity).[UniProtKB:O35129]^[13] (Microbial infection) Involved in human enterovirus 71/EV-71 infection by enhancing the autophagy mechanism during the infection.^[14]

References

1. ↑ Montano MM, Ekena K, Delage-Mourroux R, Chang W, Martini P, Katzenellenbogen BS. An estrogen receptor-selective coregulator that potentiates the effectiveness of antiestrogens and represses the activity of estrogens. Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6947-52. PMID:10359819 doi:10.1073/pnas.96.12.6947
2. ↑ Coates PJ, Nenutil R, McGregor A, Picksley SM, Crouch DH, Hall PA, Wright EG. Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence. Exp Cell Res. 2001 May 1;265(2):262-73. PMID:11302691 doi:10.1006/excr.2001.5166
3. ↑ Strub GM, Paillard M, Liang J, Gomez L, Allegood JC, Hait NC, Maceyka M, Price MM, Chen Q, Simpson DC, Kordula T, Milstien S, Lesnefsky EJ, Spiegel S. Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J. 2011 Feb;25(2):600-12. PMID:20959514 doi:10.1096/fj.10-167502
4. ↑ Fu P, Yang Z, Bach LA. Prohibitin-2 binding modulates insulin-like growth factor-binding protein-6 (IGFBP-6)-induced rhabdomyosarcoma cell migration. J Biol Chem. 2013 Oct 11;288(41):29890-900. PMID:24003225 doi:10.1074/jbc.M113.510826
5. ↑ Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B. Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor. Cell. 2017 Jan 12;168(1-2):224-238.e10. PMID:28017329 doi:10.1016/j.cell.2016.11.042
6. ↑ Yoshinaka T, Kosako H, Yoshizumi T, Furukawa R, Hirano Y, Kuge O, Tamada T, Koshiba T. Structural Basis of Mitochondrial Scaffolds by Prohibitin Complexes: Insight into a Role of the Coiled-Coil Region. iScience. 2019 Sep 27;19:1065-1078. doi: 10.1016/j.isci.2019.08.056. Epub 2019, Sep 3. PMID:31522117 doi:http://dx.doi.org/10.1016/j.isci.2019.08.056
7. ↑ Coates PJ, Nenutil R, McGregor A, Picksley SM, Crouch DH, Hall PA, Wright EG. Mammalian prohibitin proteins respond to mitochondrial stress and decrease during cellular senescence. Exp Cell Res. 2001 May 1;265(2):262-73. PMID:11302691 doi:10.1006/excr.2001.5166
8. ↑ Strub GM, Paillard M, Liang J, Gomez L, Allegood JC, Hait NC, Maceyka M, Price MM, Chen Q, Simpson DC, Kordula T, Milstien S, Lesnefsky EJ, Spiegel S. Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J. 2011 Feb;25(2):600-12. PMID:20959514 doi:10.1096/fj.10-167502
9. ↑ Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B. Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor. Cell. 2017 Jan 12;168(1-2):224-238.e10. PMID:28017329 doi:10.1016/j.cell.2016.11.042
10. ↑ Yoshinaka T, Kosako H, Yoshizumi T, Furukawa R, Hirano Y, Kuge O, Tamada T, Koshiba T. Structural Basis of Mitochondrial Scaffolds by Prohibitin Complexes: Insight into a Role of the Coiled-Coil Region. iScience. 2019 Sep 27;19:1065-1078. doi: 10.1016/j.isci.2019.08.056. Epub 2019, Sep 3. PMID:31522117 doi:http://dx.doi.org/10.1016/j.isci.2019.08.056
11. ↑ Bavelloni A, Piazzi M, Raffini M, Faenza I, Blalock WL. Prohibitin 2: At a communications crossroads. IUBMB Life. 2015 Apr;67(4):239-54. PMID:25904163 doi:10.1002/iub.1366
12. ↑ Bavelloni A, Piazzi M, Raffini M, Faenza I, Blalock WL. Prohibitin 2: At a communications crossroads. IUBMB Life. 2015 Apr;67(4):239-54. PMID:25904163 doi:10.1002/iub.1366
13. ↑ Fu P, Yang Z, Bach LA. Prohibitin-2 binding modulates insulin-like growth factor-binding protein-6 (IGFBP-6)-induced rhabdomyosarcoma cell migration. J Biol Chem. 2013 Oct 11;288(41):29890-900. PMID:24003225 doi:10.1074/jbc.M113.510826
14. ↑ Su W, Huang S, Zhu H, Zhang B, Wu X. Interaction between PHB2 and Enterovirus A71 VP1 Induces Autophagy and Affects EV-A71 Infection. Viruses. 2020 Apr 8;12(4):414. PMID:32276428 doi:10.3390/v12040414