Ydrophobic patch comprising Phe49, Trp74, Leu75, Ile85, Ile86 and Leu89, from

Ydrophobic patch comprising Phe49, Trp74, Leu75, Ile85, Ile86 and Leu89, from a2 and a3, make van der Waals interactions to equivalent residues in the partner subunit (Fig. 8). In another area, a conserved Tyr54 and Pro60 from one subunit interact with a hydrophobic core formed by Tyr54, Ile97, Ile98, Pro99, Leu102 and Leu121 from a3 and a5 of the partner subunit (Fig. 7). Other hydrophobic residues extending across the dimer interface include Leu52, Leu64, Leu67, Val90 and Val118 (not shown). The strictly conserved pair of residues Pro60 and Pro99, already mentioned as contributing to the inter-subunit hydrophobic associations, are positioned 15481974 at the start of a2 and a4 respectively (Fig. 7), and likely important to initiate formation of the two helices.Function of the SCAN Domain68181-17-9 site transcription factors form complexes that regulate the expression of target genes. For example, the proto-oncogene Jun, belonging to the basic region-leucine zipper (bZIP) family, regulates gene transcription in a specific manner by forming homo- and heterodimers. It is the combination of dimerization state and binding partners that determine activity and DNAbinding site preferences [42]. Similar control of transcription has been observed in some Cys2-His2 zinc finger containing transcription factors that contain a protein-protein binding BTB/POZ domain. Self-oligomerization of this domain in theGAGA transcription factor promotes DNA binding affinity and specificity [43]. The SCAN domain may be playing a similar regulatory role in mammalian gene expression by mediating both homo- and selective hetero-dimerization of Cys2-His2 zinc finger proteins. To date, there are no data to suggest that SCAN domains participate 1315463 directly in transcriptional activation or repression. The possibility that PEG3 could homodimerize through the SCAN domain suggests however that PEG3 binds to at least some target genes as a homodimer. In particular, this might be a prerequisite for PEG3 binding palindromic DNA motifs. Consistent with this is the finding that the Zfp206 transcription factor can form a homodimer using its SCAN domain and binds to a palindromic sequence [26,44]. A 15 base pair non-palindromic DNA binding motif for PEG3 was predicted and subsequently validated using electromobility shift and promoter assays [8]. Although the fulllength motif was required for maximal binding, PEG3 was observed to bind to the partial sequence as well as to other regions with degenerate sequence. The DNA binding selectivity and affinity of PEG3 might depend on its specific isoform. To date, there are four known PEG3 isoforms. One isoform contains only two Cys2-His2 zinc finger motifs, while in two other isoforms the SCAN domain is absent. Thus, the presence or absence of the SCAN domain and varying number of zinc finger motifs provides a potential additional control mechanism. A number of SCAN domain members have been reported to selectively interact with other SCAN members [23?6]. However, it has not been shown that PEG3-SCAN can form heterodimers. Superposition of a PEG3SCAN subunit on the Zfp206 dimer structure shows a close fit and SPDB spatial conservation of key residues forming the intermolecular contacts (Fig. 2, Fig. 4, data not shown), suggesting the possibility that the PEG3-SCAN domain might form a heterodimer with Zfp206 as well as with other SCAN domain containing proteins. Future studies, focusing on the binding partners of PEG3-SCAN are required to inform on the role of PEG3 in ge.Ydrophobic patch comprising Phe49, Trp74, Leu75, Ile85, Ile86 and Leu89, from a2 and a3, make van der Waals interactions to equivalent residues in the partner subunit (Fig. 8). In another area, a conserved Tyr54 and Pro60 from one subunit interact with a hydrophobic core formed by Tyr54, Ile97, Ile98, Pro99, Leu102 and Leu121 from a3 and a5 of the partner subunit (Fig. 7). Other hydrophobic residues extending across the dimer interface include Leu52, Leu64, Leu67, Val90 and Val118 (not shown). The strictly conserved pair of residues Pro60 and Pro99, already mentioned as contributing to the inter-subunit hydrophobic associations, are positioned 15481974 at the start of a2 and a4 respectively (Fig. 7), and likely important to initiate formation of the two helices.Function of the SCAN DomainTranscription factors form complexes that regulate the expression of target genes. For example, the proto-oncogene Jun, belonging to the basic region-leucine zipper (bZIP) family, regulates gene transcription in a specific manner by forming homo- and heterodimers. It is the combination of dimerization state and binding partners that determine activity and DNAbinding site preferences [42]. Similar control of transcription has been observed in some Cys2-His2 zinc finger containing transcription factors that contain a protein-protein binding BTB/POZ domain. Self-oligomerization of this domain in theGAGA transcription factor promotes DNA binding affinity and specificity [43]. The SCAN domain may be playing a similar regulatory role in mammalian gene expression by mediating both homo- and selective hetero-dimerization of Cys2-His2 zinc finger proteins. To date, there are no data to suggest that SCAN domains participate 1315463 directly in transcriptional activation or repression. The possibility that PEG3 could homodimerize through the SCAN domain suggests however that PEG3 binds to at least some target genes as a homodimer. In particular, this might be a prerequisite for PEG3 binding palindromic DNA motifs. Consistent with this is the finding that the Zfp206 transcription factor can form a homodimer using its SCAN domain and binds to a palindromic sequence [26,44]. A 15 base pair non-palindromic DNA binding motif for PEG3 was predicted and subsequently validated using electromobility shift and promoter assays [8]. Although the fulllength motif was required for maximal binding, PEG3 was observed to bind to the partial sequence as well as to other regions with degenerate sequence. The DNA binding selectivity and affinity of PEG3 might depend on its specific isoform. To date, there are four known PEG3 isoforms. One isoform contains only two Cys2-His2 zinc finger motifs, while in two other isoforms the SCAN domain is absent. Thus, the presence or absence of the SCAN domain and varying number of zinc finger motifs provides a potential additional control mechanism. A number of SCAN domain members have been reported to selectively interact with other SCAN members [23?6]. However, it has not been shown that PEG3-SCAN can form heterodimers. Superposition of a PEG3SCAN subunit on the Zfp206 dimer structure shows a close fit and spatial conservation of key residues forming the intermolecular contacts (Fig. 2, Fig. 4, data not shown), suggesting the possibility that the PEG3-SCAN domain might form a heterodimer with Zfp206 as well as with other SCAN domain containing proteins. Future studies, focusing on the binding partners of PEG3-SCAN are required to inform on the role of PEG3 in ge.

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