What makes a binding domain

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What makes a binding domain

One of the projects that I am busy with at the moment is writing a review about phosphoinositide binding domains. Preparing for that I have been reading old reviews on the same topic. One thing that I noticed was that some domains which have shown to bind phosphoinositides, like the CRAL-TRIO domains, were not included. The logical explaination for that will be of course that they were identified later than said review, but this was not the case. I decided, therefor, to do a bit of research into what makes a binding domain.

While the definition of a domain is clear such as shown on the InterPro website where the define a domain as follow:

“Domains are distinct functional, structural or sequence units that may exist in a variety of biological contexts.”

What defines a binding domain is harder to find, but Wikipedia tells us:

“A binding domain is a protein domain which binds to a specific atom or molecule, such as calcium or DNA. […] Binding domains are essential for the function of many proteins. They are essential because they help splice, assemble, and translate proteins.”

Under this definition we could classify all domains that have proven to function in the binding of molecule such as a lipid or a protein to be called a lipid- or protein-binding domain. This is clear and simple. So why then are some domains for which specific binding capacity is confirmed not classified as such in the literature. Two things appear to be playing a role here.

The first is that sometimes the function of the domain is less clear-cut than some articles tend to make out it to be. So there might be some ambiguity. For example, the TUBBY domain binds highly specific to bi-phosphorylated phosphoinositides. However, as part of its function, once released from its phospholipid it can translocate to the nucleus using the same domain for binding to DNA promoting transcription. Therefore, it could be classified as both a phospholipid- and a DNA-binding domain.

The second is that the domain binding behaviour is different compared to that of other binding domains binding the same type of molecule. For example, for the CRAL-TRIO domain, it is described that it binds phospholipid not only by its head group but by engulfing the whole phospholipid, head and tail. In this respect, it stands out from other phospholipid binding proteins which, in general bind the phospholipid by its head only.

So, in the end, the decision to name a domain as say a phospholipid-binding domain appears to be partly arbitrary. Depending on the level of evidence in favour and against it, but also on how easily its function fits within that single definition. Do I now know if I should include a description of the CRAL-TRIO domains in my review? No I don’t. Will I include them? I probably will as part of their definition is that they bind small lipophilic molecules. Meaning, that when investigating lipid protein interactions you should keep them in mind as potential interactors. This is what readers of the review will want to know. Therefor I should tell them all that is known about it.