tag:blogger.com,1999:blog-37148773.post8426037839434799587..comments2024-03-19T00:24:23.577-04:00Comments on <center>Sandwalk</center>: Slip Slidin' Along - How DNA Binding Proteins Find Their TargetLarry Moranhttp://www.blogger.com/profile/05756598746605455848noreply@blogger.comBlogger9125tag:blogger.com,1999:blog-37148773.post-66679425932516900442014-04-23T04:22:45.624-04:002014-04-23T04:22:45.624-04:00This comment has been removed by the author.Anonymoushttps://www.blogger.com/profile/09196026531503496681noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-53148488573811098042012-07-17T02:47:40.085-04:002012-07-17T02:47:40.085-04:00As a commentator up-thread noted, any slip-and-sli...As a commentator up-thread noted, any slip-and-slide model of sequence-specific DNA binding activity by transcription factors fails the sniff test: how is the activator (or repressor) able to effectively scan the nucleotide side-groups to achive site-specificity when the latter are coated with histones (in most eukaryotes) and with other attendant DNA-binding molecules (in all organisms). The notion that the chromosomal DNA molecule exists in all of its double-helical beauty for all proteins to probe seems rather tired and readily debunked to my mind. I've been a hesitant skeptic of the "histone code" as anything other than correlative observations, but given the ubiquitous habit of histone compaction of large chromosomal segments, some portions of which obviously remain accessible to transcription factors, it seems clear to me that we're missing some vital pieces of the puzzle.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-68160128634949280632012-07-14T21:18:52.693-04:002012-07-14T21:18:52.693-04:003D diffusion (to use your terminology) is not repl...<i>3D diffusion (to use your terminology) is not replaced by 1D diffusion.</i><br /><br />Of course it is. I haven't bothered to read the paper or its abstract when I posted the message above but now that I did, I am pleased (but not at all surprised) to find that that's exactly the terminology they use: <br /><br />"a combination of 3D diffusion in the cytoplasm and 1D diffusion (sliding) along the DNA." (first paragraph). <br /><br />I don't know what you imagine that happens (it's not at all clear from your post) but here is how it works in the physical world we live in: <br /><br />1. DNA-binding protein reaches a piece of DNA by regular 3D diffusion and binds to it ("non-specifically" - which isn't really non-specific; just a lot less specific). <br />2. Because the affinity is relatively low, it at some point (usually soon) detaches and diffuses some distance. That distance is very small because the affinity is still high enough for the the protein to quickly bind back to the DNA - but now at a slightly different position than the first time. So the observer who only pays attention to the fact that the protein remains associated with DNA most of the time can conclude that the protein "slides" alone DNA.<br />3. It's not a true sliding (although it can be modeled as such) and it most certainly is not directional - like any random diffusional process, be it in 3D (cytoplasm), 2D (membrane), or 1D (linear polymers like DNA). This is important to stress because there are certainly examples of true directional sliding (powered by motors). Overall, the simplest formalism to describe what happens is to say that the protein undergoes 1D diffusion along DNA. <br />4. The important thing that follows is that there exists an optimal strength of the non-specific binding that enables the fastest target search: bind too tightly and the "sliding" will be too slow (spend too much time stuck to the same point on DNA); bind too weakly and the "sliding" will also be too slow (too high a chance to get lost far into surrounding solution after unbinding from DNA).DKnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-38626560034717900422012-07-14T15:15:36.666-04:002012-07-14T15:15:36.666-04:003D diffusion (to use your terminology) is not repl...3D diffusion (to use your terminology) is not replaced by 1D diffusion. It's two separate processes - regular diffusion (to land somewhere very, very near the operator) plus the slip'n slide. Both together are faster than plain old regular diffusion on its own; hence the "facilitated". It's fundamentally different from the way in which some small substrate may diffuse to the active site of an enzyme.DAKhttps://www.blogger.com/profile/03441053230117075138noreply@blogger.comtag:blogger.com,1999:blog-37148773.post-82483695474943633102012-07-13T18:40:18.969-04:002012-07-13T18:40:18.969-04:00Exactly.Exactly.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-56270817299010959872012-07-13T18:39:32.866-04:002012-07-13T18:39:32.866-04:00Actually the explanation is that diffusion of the ...Actually the explanation is that diffusion of the protein to the binding site is facilitated by its sliding along the DNA strand, not that it slides "<b>until</b> it finds its binding site." The process, as should be expected, is not perfect. For one, the continuity of the sliding process depends on how long the protein can stay semi-attached to the DNA molecule. For another, there are many other proteins attaching, detaching, and or sliding on the DNA.Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-43664027759943702972012-07-13T18:30:32.748-04:002012-07-13T18:30:32.748-04:00Involves sliding, detaching, attaching again, slid...Involves sliding, detaching, attaching again, sliding ...Anonymousnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-67597886602001944462012-07-13T17:19:15.443-04:002012-07-13T17:19:15.443-04:00What actually happens is that the repressor (and ...<i>What actually happens is that the repressor (and other similar DNA binding proteins) sticks non-specifically to DNA then slides along the DNA molecule looking for a target sequence. It can scan about 50 bp of DNA in a single interaction and this form of "facilitated diffusion" leads to a much quicker search for the target sequence.</i><br /><br />In really simple terms, 3D diffusion is replaced by 1D diffusion: for any connected points A and B, 1D will always be much, much faster. 1D diffusion is still a diffusion - there is nothing "facilitated" about it.DKnoreply@blogger.comtag:blogger.com,1999:blog-37148773.post-90417560485340561192012-07-13T14:30:39.149-04:002012-07-13T14:30:39.149-04:00I think we can safely conclude that most specific ...<i> I think we can safely conclude that most specific DNA binding proteins find their target sites by binding non-specifically to DNA then sliding along the double-stranded helix until they find their specific binding site.</i><br /><br />Does the above statement include eukaryotic transcription factors? It is much more difficult to see how that works when you have nucleosomes.Georgi Marinovhttps://www.blogger.com/profile/12226357993389417752noreply@blogger.com