This depends on what your goal is and how big the 2 domains are. The linker might influence the interaction between the 2 domains. That is why you want to use a flexible linker. Flexible linkers are Gly Ser rich, for example (GGS)4, or GGGGS, ...

If you want to purify your chimeric protein afterwards (which i am assuming you want to) and you didn't include a tag yet, you can opt for an internal 6HIS-tag. This however should also be combined with a flexible linker since it otherwise won't be accessible enough to bind the resin. An internal strep2-tag might also be possible, however the same accessibility issue might occur.

If you want to separate the two domains afterwards again, you can use a cleavage site (thrombin recognition sequence for example). But be aware that a problem with many commercial thrombin sources is secondary protease activity.

Hope this helps !

Dear Vanmeert,

Thank you so much for your response, your answer was really complete and helpful.

Here is a papers on linkers for recombinant protein design and expression. I hope it helps to fix your problems.

Article Design strategies to address the effect of hydrophobic epito...

Article Fusion Protein Linkers: Property, Design and Functionality