| Structural highlights
Function
[LDB1_XENLA] Binds to the LIM domain of a wide variety of LIM domain-containing transcription factors. Acts as a coactivator together with otx2 to stimulate lhx1/lim1-mediated activation of the gsc promoter in the Spemann organizer. Acts synergistically with lhx1/lim1 and ssbp in axis formation.[1] [2] [3]
Publication Abstract from PubMed
The Chip/LIM-domain binding protein (LDB)-single-stranded DNA-binding protein (SSDP) (ChiLS) complex controls numerous cell-fate decisions in animal cells, by mediating transcription of developmental control genes via remote enhancers. ChiLS is recruited to these enhancers by lineage-specific LIM-domain proteins that bind to its Chip/LDB subunit. ChiLS recently emerged as the core module of the Wnt enhanceosome, a multiprotein complex that primes developmental control genes for timely Wnt responses. ChiLS binds to NPFxD motifs within Pygopus (Pygo) and the Osa/ARID1A subunit of the BAF chromatin remodeling complex, which could synergize with LIM proteins in tethering ChiLS to enhancers. Chip/LDB and SSDP both contain N-terminal dimerization domains that constitute the bulk of their structured cores. Here, we report the crystal structures of these dimerization domains, in part aided by DARPin chaperones. We conducted systematic surface scanning by structure-designed mutations, followed by in vitro and in vivo binding assays, to determine conserved surface residues required for binding between Chip/LDB, SSDP, and Pygo-NPFxD. Based on this, and on the 4:2 (SSDP-Chip/LDB) stoichiometry of ChiLS, we derive a highly constrained structural model for this complex, which adopts a rotationally symmetrical SSDP2-LDB2-SSDP2 architecture. Integrity of ChiLS is essential for Pygo binding, and our mutational analysis places the NPFxD pockets on either side of the Chip/LDB dimer, each flanked by an SSDP dimer. The symmetry and multivalency of ChiLS underpin its function as an enhancer module integrating Wnt signals with lineage-specific factors to operate context-dependent transcriptional switches that are pivotal for normal development and cancer.
Rotational symmetry of the structured Chip/LDB-SSDP core module of the Wnt enhanceosome.,Renko M, Fiedler M, Rutherford TJ, Schaefer JV, Pluckthun A, Bienz M Proc Natl Acad Sci U S A. 2019 Sep 30. pii: 1912705116. doi:, 10.1073/pnas.1912705116. PMID:31570581[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mochizuki T, Karavanov AA, Curtiss PE, Ault KT, Sugimoto N, Watabe T, Shiokawa K, Jamrich M, Cho KW, Dawid IB, Taira M. Xlim-1 and LIM domain binding protein 1 cooperate with various transcription factors in the regulation of the goosecoid promoter. Dev Biol. 2000 Aug 15;224(2):470-85. PMID:10926781 doi:http://dx.doi.org/10.1006/dbio.2000.9778
- ↑ Chen L, Segal D, Hukriede NA, Podtelejnikov AV, Bayarsaihan D, Kennison JA, Ogryzko VV, Dawid IB, Westphal H. Ssdp proteins interact with the LIM-domain-binding protein Ldb1 to regulate development. Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14320-5. doi:, 10.1073/pnas.212532399. Epub 2002 Oct 15. PMID:12381786 doi:http://dx.doi.org/10.1073/pnas.212532399
- ↑ Agulnick AD, Taira M, Breen JJ, Tanaka T, Dawid IB, Westphal H. Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature. 1996 Nov 21;384(6606):270-2. PMID:8918878 doi:http://dx.doi.org/10.1038/384270a0
- ↑ Renko M, Fiedler M, Rutherford TJ, Schaefer JV, Pluckthun A, Bienz M. Rotational symmetry of the structured Chip/LDB-SSDP core module of the Wnt enhanceosome. Proc Natl Acad Sci U S A. 2019 Sep 30. pii: 1912705116. doi:, 10.1073/pnas.1912705116. PMID:31570581 doi:http://dx.doi.org/10.1073/pnas.1912705116
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