Febs Letters Volume 93, Number 1-2./Volume 94, Number 1-2. [antikvár]

Volume 93, number 1FEBS LETTERSSeptember 1978Review LetterINTER-DOMAIN MOBILITY IN PROTEINS AND ITS PROBABLE FUNCTIONAL ROLEO. B. PTITSYNInstitute of Protein Research, Academy of Sciences of the USSR, 142292 Poustchino, Moscow Region, USSRReceived 22 May 19781. Domain mechanism of protein foldingIn 1973 [1,2] we suggested (see also [3]) that a polypeptide chain of a globular protein can fold by the independent initiation and growth of two 'crystallization centers' of its tertiary structure. The compact structure of a protein as a whole is formed at the last stage of folding by the pre-existing structure merging of the two halves of a protein molecule. In the same year Wetlaufer [4] noticed that large proteins usually consist of two (or several) domains. He suggested that each of the domains folds independently.Wetlaufer [4] defined domains as distinct structural compact regions which could be completely encircled by a closed surface. Later Rossman and Liljas [5] proposed a simple method of locating domains by distance maps (matrices of the distances between C^,-atoms of all monomer residues [6]). They noticed that different domains of some proteins have different functions (e.g., NAD-binding and catalytic functions in dehydrogenases). Later the functional role of domains was thoroughly considered in the review [7].The term 'domain' as used, for example, in papers [4,5] has not only a geometrical but also an energetical meaning implying that inter-domain interactions are weaker than intra-domain ones. This is undoubtedly the case at least in some proteins (e.g., in phospho-glycerate kinase [8] and hexokinase [9]) which are evidently divided into two lobes and very probably it may be a general feature of domain-containing proteins. This makes the hypothesis about the independent folding of domains rather convincing. This hypothesis explains the high cooperativity of the folding of large proteins [10] because the folding of each domain is a cooperative process and the stabilityof separate domains (before their merging into the structural entity) is usually low.However in some cases (e.g., in immunoglobins [11] and in troponin C [12]) separate domains are stable enough to remain in the folded state even after the enzymatic cleavage of the protein into two or more domains. Recent calorimetric data show that domains of some proteins, e.g., immunoglobin [13] or papain (E. 1. Tiktopulo and P. L. Privalov, to be pubhshed) can unfold and refold independently. This suggests that the most stable intermediate states of partially folded large proteins are separate folded domains [10]. Very recently this hypothesis was directly confirmed for hen-egg lysozyme. It was shown by direct X-ray analysis [14] that partly refolded lysozyme (in 0.35 M sodium dodecyl sulfate) differs from the native one mainly in that the two domains of this protein move away from each other. The main features of the internal structure of both domains are retained.2. Inter-domain mobility in protein moleculesIf inter-domain interactions are in fact relatively small, one can anticipate the existence of domain displacements not only under denaturing influences but also under other ones. Indeed, X-ray data show the existence of minor but measurable relative domain displacements in hen-egg lysozyme after the binding of the competitive inhibitor [15] or in chymotrypsinogen after its activation into a-chymo-trypsin [16]. Model calculations for lysozyme [17] and subtilysin [18] also demonstrated that their domains can be relatively easily displaced. Much moreElsevierfNorth-Holland Biomedical PressI