| Structural highlights
Function
SP1_HUMAN Transcription factor that can activate or repress transcription in response to physiological and pathological stimuli. Binds with high affinity to GC-rich motifs and regulates the expression of a large number of genes involved in a variety of processes such as cell growth, apoptosis, differentiation and immune responses. Highly regulated by post-translational modifications (phosphorylations, sumoylation, proteolytic cleavage, glycosylation and acetylation). Binds also the PDGFR-alpha G-box promoter. May have a role in modulating the cellular response to DNA damage. Implicated in chromatin remodeling. Plays a role in the recruitment of SMARCA4/BRG1 on the c-FOS promoter. Plays an essential role in the regulation of FE65 gene expression. In complex with ATF7IP, maintains telomerase activity in cancer cells by inducing TERT and TERC gene expression.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Publication Abstract from PubMed
The mimicry of protein tertiary folds by chains artificial in backbone chemical composition leads to proteomimetic analogues with potential utility as bioactive agents and as tools to shed light on biomacromolecule behavior. Notable successes toward such molecules have been achieved; however, as protein structural diversity is vast, design principles must be continually honed as they are applied to new prototype folding patterns. One specific structure where a gap remains in understanding how to effectively generate modified backbone analogues is the metal-binding beta-turn found in zinc finger domains. Literature precedent suggests several factors that may act in concert, including the artificial moiety used to modify the turn, the sequence in which it is applied, and modifications present elsewhere in the domain. Here, we report efforts to gain insights into these issues and leverage these insights to construct a zinc finger mimetic with backbone modifications throughout its constituent secondary structures. We first conduct a systematic comparison of four turn mimetics in a common host sequence, quantifying relative efficacy for use in a metal-binding context. We go on to construct a proteomimetic zinc finger domain in which the helix, strands, and turn are simultaneously modified, resulting in a variant with 23% artificial residues, a tertiary fold indistinguishable from the prototype, and a folded stability comparable to the natural backbone on which the variant is based. Collectively, the results reported provide new insights into the effects of backbone modification on structure and stability of metal-binding domains and help inform the design of metalloprotein mimetics.
Proteomimetic Zinc Finger Domains with Modified Metal-binding beta-Turns.,Rao SR, Horne WS Pept Sci (Hoboken). 2020 Sep;112(5). doi: 10.1002/pep2.24177. Epub 2020 Jun 7. PMID:33733039[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Yang X, Su K, Roos MD, Chang Q, Paterson AJ, Kudlow JE. O-linkage of N-acetylglucosamine to Sp1 activation domain inhibits its transcriptional capability. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6611-6. Epub 2001 May 22. PMID:11371615 doi:http://dx.doi.org/10.1073/pnas.111099998
- ↑ Milanini-Mongiat J, Pouyssegur J, Pages G. Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J Biol Chem. 2002 Jun 7;277(23):20631-9. Epub 2002 Mar 19. PMID:11904305 doi:http://dx.doi.org/10.1074/jbc.M201753200
- ↑ Bonello MR, Khachigian LM. Fibroblast growth factor-2 represses platelet-derived growth factor receptor-alpha (PDGFR-alpha) transcription via ERK1/2-dependent Sp1 phosphorylation and an atypical cis-acting element in the proximal PDGFR-alpha promoter. J Biol Chem. 2004 Jan 23;279(4):2377-82. Epub 2003 Oct 30. PMID:14593115 doi:http://dx.doi.org/10.1074/jbc.M308254200
- ↑ Hsu MC, Chang HC, Hung WC. HER-2/neu represses the metastasis suppressor RECK via ERK and Sp transcription factors to promote cell invasion. J Biol Chem. 2006 Feb 24;281(8):4718-25. Epub 2005 Dec 23. PMID:16377629 doi:http://dx.doi.org/10.1074/jbc.M510937200
- ↑ Vicart A, Lefebvre T, Imbert J, Fernandez A, Kahn-Perles B. Increased chromatin association of Sp1 in interphase cells by PP2A-mediated dephosphorylations. J Mol Biol. 2006 Dec 15;364(5):897-908. Epub 2006 Sep 16. PMID:17049555 doi:http://dx.doi.org/10.1016/j.jmb.2006.09.036
- ↑ Hung JJ, Wang YT, Chang WC. Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. Mol Cell Biol. 2006 Mar;26(5):1770-85. PMID:16478997 doi:http://dx.doi.org/10.1128/MCB.26.5.1770-1785.2006
- ↑ Zhang Y, Liao M, Dufau ML. Phosphatidylinositol 3-kinase/protein kinase Czeta-induced phosphorylation of Sp1 and p107 repressor release have a critical role in histone deacetylase inhibitor-mediated derepression [corrected] of transcription of the luteinizing hormone receptor gene. Mol Cell Biol. 2006 Sep;26(18):6748-61. PMID:16943418 doi:http://dx.doi.org/10.1128/MCB.00560-06
- ↑ Olofsson BA, Kelly CM, Kim J, Hornsby SM, Azizkhan-Clifford J. Phosphorylation of Sp1 in response to DNA damage by ataxia telangiectasia-mutated kinase. Mol Cancer Res. 2007 Dec;5(12):1319-30. doi: 10.1158/1541-7786.MCR-07-0374. PMID:18171990 doi:http://dx.doi.org/10.1158/1541-7786.MCR-07-0374
- ↑ Chung SS, Kim JH, Park HS, Choi HH, Lee KW, Cho YM, Lee HK, Park KS. Activation of PPARgamma negatively regulates O-GlcNAcylation of Sp1. Biochem Biophys Res Commun. 2008 Aug 8;372(4):713-8. doi:, 10.1016/j.bbrc.2008.05.096. Epub 2008 May 28. PMID:18513490 doi:http://dx.doi.org/10.1016/j.bbrc.2008.05.096
- ↑ Spengler ML, Guo LW, Brattain MG. Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation. Cell Cycle. 2008 Mar 1;7(5):623-30. Epub 2007 Dec 4. PMID:18239466
- ↑ Iwahori S, Yasui Y, Kudoh A, Sato Y, Nakayama S, Murata T, Isomura H, Tsurumi T. Identification of phosphorylation sites on transcription factor Sp1 in response to DNA damage and its accumulation at damaged sites. Cell Signal. 2008 Oct;20(10):1795-803. doi: 10.1016/j.cellsig.2008.06.007. Epub, 2008 Jun 19. PMID:18619531 doi:http://dx.doi.org/10.1016/j.cellsig.2008.06.007
- ↑ Chuang JY, Wang YT, Yeh SH, Liu YW, Chang WC, Hung JJ. Phosphorylation by c-Jun NH2-terminal kinase 1 regulates the stability of transcription factor Sp1 during mitosis. Mol Biol Cell. 2008 Mar;19(3):1139-51. doi: 10.1091/mbc.E07-09-0881. Epub 2008, Jan 16. PMID:18199680 doi:http://dx.doi.org/10.1091/mbc.E07-09-0881
- ↑ Jochmann R, Thurau M, Jung S, Hofmann C, Naschberger E, Kremmer E, Harrer T, Miller M, Schaft N, Sturzl M. O-linked N-acetylglucosaminylation of Sp1 inhibits the human immunodeficiency virus type 1 promoter. J Virol. 2009 Apr;83(8):3704-18. doi: 10.1128/JVI.01384-08. Epub 2009 Feb 4. PMID:19193796 doi:http://dx.doi.org/10.1128/JVI.01384-08
- ↑ Yu HT, Chan WW, Chai KH, Lee CW, Chang RC, Yu MS, McLoughlin DM, Miller CC, Lau KF. Transcriptional regulation of human FE65, a ligand of Alzheimer's disease amyloid precursor protein, by Sp1. J Cell Biochem. 2010 Mar 1;109(4):782-93. doi: 10.1002/jcb.22457. PMID:20091743 doi:http://dx.doi.org/10.1002/jcb.22457
- ↑ Rao SR, Horne WS. Proteomimetic Zinc Finger Domains with Modified Metal-binding beta-Turns. Pept Sci (Hoboken). 2020 Sep;112(5). doi: 10.1002/pep2.24177. Epub 2020 Jun 7. PMID:33733039 doi:http://dx.doi.org/10.1002/pep2.24177
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