Miracle of multi-domain proteins: a case study of ROCK kinase

Dvorsky R., Badri Nath Dubey

Institute of Biochemistry and Molecular Biology II, Heinrich-Heine University, Düsseldorf, Germany

Globular polymer molecule is an archetypal image of proteins presented in all school books. But many proteins consist of several such globular subunits called domains. In fact, majority of proteins have multi-domain architecture so that the archetypal protein image should be revisited. Moreover, proteins often lack conventional globular fold in some of their parts. If they are unstructured, polypeptide chain forms random coil; most typical fold of structured non-globular domain is coiled-coil.

ROCK kinases belong to the proteins possessing coiled-coil fold in a large extent - own kinase domain comprises only about 30% of its 1354 residues while coiled-coil motif 45%. More then a decade of effort has been dedicated to a very simple question: how the structure of whole ROCK kinase looks like. As it is (currently?) impossible to determine the structure of such large protein at once we are reliant on the combination of various techniques. How such combination helped us to construct the model of full-length ROCK kinase (Fig. 1) and can in general help to answer that very basic question crucial for myriad of proteins will be presented during the talk.

Fig. 1: Overall model of full-length ROCK kinase

This, however, is still just one part of the story. Second part, perhaps even more essential, is the relationship between the overall architecture of multu-domain protein and its function. How far have we come in this aspect concerning ROCK kinase will be also discussed. Putting it in the context of whole family of protein will finally demonstrate that the understanding of the interplay of diverse domains within the proteins is generally a next, level-up challenge in biology.