Structural evolution of C-terminal domains in the p53 family

Ou, Horng D.; Löhr, Frank; Vogel, Vitali; Mäntele, Werner; Dötsch, Volker

doi:10.1038/sj.emboj.7601764

Cited by 86 publications

(100 citation statements)

References 47 publications

(55 reference statements)

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“…p63 possibly encodes for the more ancient form of the p53 family and might be thus most related to cep-1. Besides structural considerations this notion is further supported by the more recent fi nding that p63 acts analogously to CEP-1 to speci fi cally affect DNA damage-induced apoptosis in the female mammalian germline (Suh et al 2006 ;Ou et al 2007 ) . The C. elegans p53-like protein CEP-1 turned out to be a direct transcriptional activator of egl-1 and a second BH3-only protein called CED-13 (Schumacher et al 2005a ) (Fig.…”

Section: Pathways Leading To Dna Damage-induced Apoptosismentioning

confidence: 85%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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In the past 12 years, since the fi rst description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing.

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Section: Pathways Leading To Dna Damage-induced Apoptosismentioning

confidence: 85%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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“…1,12,18 This bewildering array of different proteins becomes even more complex by the fact that all members of this family -with the exception of the C. elegans protein Cep-1 (ref. 19) -contain an oligomerization domain (OD) that is capable of forming tetramers, thus allowing the formation of a potentially astronomical number of different protein species. The high sequence identity within the ODs among the different family members increases this theoretical number even further by potentially enabling the formation of hetero-oligomers that contain different combinations of isoforms of these family members.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

et al. 2016

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Members of the p53 tumor-suppressor family are expressed as multiple isoforms. Isoforms with an N-terminal transactivation domain are transcriptionally active, while those ones lacking this domain often inhibit the transcriptional activity of other family members. In squamous cell carcinomas, the high expression level of ΔNp63α inhibits the tumor-suppressor function of TAp73β. This can in principle be due to blocking of the promoter or by direct interaction between both proteins. p63 and p73 can heterooligomerize through their tetramerization domains and a hetero-tetramer consisting of two p63 and two p73 molecules is thermodynamically more stable than both homo-tetramers. Here we show that cells expressing both p63 and p73 exist in mouse epidermis and hair follicle and that hetero-tetramer complexes can be detected by immunoprecipitation in differentiating keratinocytes. Through structure determination of the hetero-tetramer, we reveal why this hetero-tetramer is the thermodynamically preferred species. We have created mutants that exclusively form either hetero-tetramers or homo-tetramers, allowing to investigate the function of these p63/p73 hetero-tetramers. Using these tools, we show that inhibition of TAp73β in squamous cell carcinomas is due to promoter squelching and not direct interaction.

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“…The procedure used to identify intermonomer and interdimer NOEs has been described before. 26 The structure is based on 908 intrasubunit NOEs, 340 intersubunit NOEs within a dimer and 242 intersubunit NOEs across the tetrameric interface. A total of 20 structures were calculated in 8 iterations, and 100 structures were calculated in the last iteration.…”

Section: Methodsmentioning

confidence: 99%

“…Structure determination of the C-termini of CEP-1 and Dmp53 showed that both proteins contain an OD, however, with architectures different from that of p53. 26 In particular, we showed that CEP-1 is the first known dimeric member of this protein family and that its OD is structurally coupled to a SAM domain. Dmp53 showed yet another architecture.…”

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confidence: 97%

“…Its tetrameric state is stabilized by an additional N-terminal b-strand and an additional C-terminal a-helix, thus doubling all secondary structure elements present in the p53 OD. 26 These structure determinations of the ODs of invertebrate forms have cast the first doubt on the universal structural role of the p53 OD. These results, combined with the high sequence conservation of B20 amino acids C-terminal to the OD of p63 and p73 (Figure 1), and the fact that p63 inhibits the transcriptional activity of p73 and directly binds to it in head and neck squamous cell carcinoma, 11 prompted us to reinvestigate the structure of the OD of these two proteins.…”

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confidence: 99%

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Conformational stability and activity of p73 require a second helix in the tetramerization domain

et al. 2009

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p73 and p63, the two ancestral members of the p53 family, are involved in neurogenesis, epithelial stem cell maintenance and quality control of female germ cells. The highly conserved oligomerization domain (OD) of tumor suppressor p53 is essential for its biological functions, and its structure was believed to be the prototype for all three proteins. However, we report that the ODs of p73 and p63 differ from the OD of p53 by containing an additional a-helix that is not present in the structure of the p53 OD. Deletion of this helix causes a dissociation of the OD into dimers; it also causes conformational instability and reduces the transcriptional activity of p73. Moreover, we show that ODs of p73 and p63 strongly interact and that a large number of different heterotetramers are supported by the additional helix. Detailed analysis shows that the heterotetramer consisting of two homodimers is thermodynamically more stable than the two homotetramers. No heterooligomerization between p53 and the p73/p63 subfamily was observed, supporting the notion of functional orthogonality within the p53 family. p53, a well-known tumor suppressor that is mutated in more than 50% of all human tumors, induces genes leading either to cell-cycle arrest or to apoptosis. The discovery of two proteins with a high sequence identity to p53, called p63 and p73, has sparked speculations that tumor suppression is carried out by the combined action of several members of this protein family, for example, by direct interaction through heterooligomerization. Knockout mouse studies with p63 and p73, the two ancestral members, 1 have shown functional roles distinct from p53: p63 is essential for maintaining epithelial stem cells 2,3 and for protecting the genomic stability of oocytes, 4 whereas p73 is involved in neurogenesis, sensory pathways and homeostatic control. 5 p73 is further known as an important inducer of apoptosis in response to DNA damage. 6 Although only few mutations of p63 and p73 have been found in human tumors so far, overexpression of p63 is often observed in squamous cell carcinoma, 7-10 which has been shown to suppress p73-dependent apoptosis. 11 Among all p53 family members, including those from invertebrate species, the DNA binding domain is the most conserved domain, 12-15 followed by the oligomerization domain (OD), which is indispensable for the biological function of all p53 protein family members. [16][17][18] It is a structural domain that forms a tetramer, and mutations within the OD that inhibit tetramerization of p53 result in greatly reduced transcriptional activity. 19 In addition, several protein-protein interactions and posttranslational modifications require the tetrameric state as well, 16 and mutations in the OD of p53 that prevent oligomerization have been identified in human cancers. 20,21 Owing to its functional importance, the OD of p53 has been the target of several structure determination projects. 22,23 The p53 tetramer consists of a dimer of dimers, with each monomer contributing one b-strand and o...

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Structural evolution of C-terminal domains in the p53 family

Cited by 86 publications

References 47 publications

Germ Cell Apoptosis and DNA Damage Responses

Germ Cell Apoptosis and DNA Damage Responses

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

Conformational stability and activity of p73 require a second helix in the tetramerization domain

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