title: Facilitated DNA search by multidomain transcription factors: cross talk via a flexible linker.
abstract: More than 70% of eukaryotic proteins are composed of multiple domains. However, most studies of the search for DNA focus on individual protein domains and do not consider potential cross talk within a multidomain transcription factor. In this study, the molecular features of the DNA search mechanism were explored for two multidomain transcription factors: human Pax6 and Oct-1. Using a simple computational model, we compared a DNA search of multidomain proteins with a search of isolated domains. Furthermore, we studied how manipulating the binding affinity of a single domain to DNA can affect the overall DNA search of the multidomain protein. Tethering the two domains via a flexible linker increases their affinity to the DNA, resulting in a higher propensity for sliding along the DNA, which is more significant for the domain with the weaker DNA-binding affinity. In this case, the domain that binds DNA more tightly anchors the multidomain protein to the DNA and, via the linker, increases the local concentration of the weak DNA-binding domain (DBD). The tethered domains directly exchange between two parallel DNA molecules via a bridged intermediate, where intersegmental transfer is promoted by the weaker DBD. We found that, in general, the relative affinity of the two domains can significantly affect the cross talk between them and thus their overall capability to search DNA efficiently. The results we obtained by examining various multidomain DNA-binding proteins support the necessity of discrepancies between the DNA-binding affinities of the constituent domains.
authors: Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
authors: Dana
authors: D
authors: Vuzman
authors: Michal
authors: M
authors: Polonsky
authors: Yaakov
authors: Y
authors: Levy
mesh_terms: D004247:DNA / Q000378:metabolism*; D004058:Diffusion; D005136:Eye Proteins / Q000737:chemistry* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D050811:Octamer Transcription Factor-1 / Q000737:chemistry* / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism*; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D050811:Octamer Transcription Factor-1; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; C494165:POU2F1 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D004247:DNA