I'd like to know more about pseudokinases. I have read a handful of papers but I want to know why they are classified as kinases in the first place if they do not have the essential activity. What is the difference between a pseudokinase and an atypical kinase. The protein that I am working on has a pseudokinase domain. Running an MSA did not show up anything worth noting. Please tell me how to proceed
Pseudokinases have sequence homology to other kinases but lack kinase activity (often due to the alteration of key catalytic residues). Atypical kinases lack sequence homology to other kinases but yet have demonstrated kinase activity.
As Andrew said, pseudokinases are proteins that appear to have a kinase domain (at the sequence level) and fold (at the structure level), but do not have kinase catalytic activity, i.e. they do not perform phosphorylation on their own. Sometimes they are have other functions, though, like activating another kinase or forming a complex.
Atypical kinases do not have complete sequence homology to the "typical" eukaryotic protein kinase (ePK) domain, but they still have kinase activity. They may match a portion of the kinase domain, e.g. the ATP-binding N-lobe, but the substrate-binding C-lobe is incomplete and not all of the 11 conserved ePK subdomains are present. The difference is visible at the structure level; in some cases the fold looks completely different.
More recently, some of the atypical kinase families have been integrated into a broader classification called the protein-kinase-like (PKL) superfamily. See:
You'll need to explain a bit on how the MSA showed nothing. There are eleven critical sub-domains within the ~250-300 amino acid protein kinase catalytic domain, assuming that you are talking about serine/threonine/tyrosine kinases of eukaryotes. These kinases and their sub-domains were defined over twenty years ago by Hunter and Hanks. In my view, which is shared by many, a significant alteration in any of these sub-domains can render a kinase non-functional or semi-functional. So, look carefully at your MSA and see which residues you have at Hunter's eleven sub-domains and if that residue is not present, closely look to see that the MSA is of high quality and that the "altered" residue (eg, the single E of sub-domain III) is not present a couple residues away. This is important because spacing between domains can vary and an alignment may not place these critical in the same column.
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Of course, you can always align your protein to the solved structure of another true kinase to see where or how placement of these above residues (as they are critical for catalytic function) and others differ or match those in the true kinase. Actually, if you're looking for function, then you need to go to structure because sequence dictates structure and structure dictates function. Thus, an MSA might not be so informative until you take it to structure.
