Molecular Biology: Protein Structure and Functions - Stepanov V.M. 2005

Tertiary protein structure
Protein domains

At first glance, the way Proteins organize their Spatial Structure—forming a Hydrophobic core and a mosaic surface containing both hydrophilic and hydrophobic elements—appears to limit the size of the globule. This is because, as its volume increases, the strictly hydrophobic core would account for a progressively smaller fraction. To some extent this is true, but this limitation affects only the size of a structure organized in this manner, rather than the molecule as a whole. Indeed, starting at a molecular mass of approximately 14-16 kDa, There is a clear tendency for a protein molecule to form from two (or more) independently folded globules, each possessing its own hydrophobic core. Such globules—domains—are formed by different segments of the same polypeptide chain.

Domains in proteins are regions within the tertiary structure that exhibit a certain degree of structural autonomy. This autonomy is sometimes so pronounced that domains can maintain and even form their spatial structure independently of other PARTS OF THE protein molecule. In many cases, domains can be separated by subjecting the protein to Limited proteolysis.

Within the context of a protein's biological function, domains frequently—though not always—perform distinct tasks, in which case structural autonomy is complemented by functional autonomy. For example, the nucleotide-binding domain of dehydrogenases, which features the same polypeptide chain folding pattern regardless of the specific function of a given enzyme, is responsible for interacting with one of the reaction substrates: the coenzyme NAD or NADH. The amino-terminal domains (kringles) of Blood Coagulation Enzymes mediate binding to Membrane Lipids and other proteins (Fig. 6.4), while the amino-terminal domains of IMMUNOGLOBULINS form the antigen-binding site.

However, in A number of cases, a distinct functional role cannot be assigned to domains. For instance, The structure of the proteolytic enzyme Papain clearly reveals two domains, each with a hydrophobic core. In the N-terminal domain, the core contains two valine residues, two isoleucine residues, and one leucine residue; in the C-terminal domain, it contains two valine residues, two leucine residues, and five phenylalanine residues. A series of hydrophobic interactions are established between the domains, which are connected by a continuous peptide chain. The cleft separating the domains houses the catalytic center, with the functional groups that form it located in both domains. It is possible that in the Cytology/cytology/16.html">Early stages of papain evolution the domains possessed some functional autonomy, but this has been entirely lost in the modern enzyme (Fig. 6.5).

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Fig. 6.4. Tertiary Structure of one of the prothrombin domains.

Upon activation, this domain—the first kringle (residues 66-144)—mediates prothrombin binding to Phospholipids. The bends in the "ribbon" correspond to the a-carbon atoms of amino acid residues; Disulfide Bonds are shown in black. The tertiary structure of other kringles—functionally specialized domains in hemostasis enzymes (There are two in Thrombin and five in plasminogen)—is presumably similar.

Most often, domains are formed by the autonomous folding of sequentially arranged Regions of the polypeptide chain, although cases are known where the Spatial structure of a domain is formed by two widely separated segments of the protein's Primary Structure.

The presence of domains presumably provides the structural preconditions for greater internal flexibility and dynamics of protein molecules compared to a single unified spatial structure, achieved through the relative displacement of domains. The zones adjacent to the interdomain contact form, as a first approximation, a cleft encircling the protein. This facilitates the positioning of sites for specific protein binding of various ligands and the dehydration of the latter.

It is hypothesized that domains correspond to an early stage in the Evolution of the spatial structure of many proteins that evolved from significantly smaller globules. For example, the unusually small HUMAN IMMUNODEFICIENCY VIRUS (HIV) proteinase, whose peptide chain consists of only 99 amino acid residues, folds in a manner similar to the domains of Pepsin—a proteinase operating via a similar mechanism. Since HIV proteinase is active only as a dimer, it can be suggested that it is evolutionarily related to some ancient precursor of pepsin domains. Interestingly, domain boundaries often correspond to exon boundaries, which again suggests they may have served as building blocks during Introduction/18.html">Protein Evolution.

Fig. 6.5. Domains in the STRUCTURE OF THE papaya proteolytic enzyme, papain. Dashed lines outline the direction of the cleft between the two domains, where the substrate binds and the catalytic center is located. The peptide chain completes The formation of the N-terminal domain by the 110th residue and begins forming the C-terminal domain from the 111th. Interaction between the domains is enhanced by the fact that the 1-16 region of the N-terminal domain contacts the C-terminal domain, while the C-terminal fragment of the latter (residues 208-212) contacts the N-terminal domain. The catalytic center includes the Cys-25 residue (in the N-terminal domain), His-159, and Asn-175 (both in the C-terminal domain). Disulfide bonds are indicated by hatched rectangles.

Domains constitute a sublevel of protein structural Organization on the pathway from secondary to tertiary structure, and the folding of sufficiently large protein globules during METABOLISM/35.html">Protein Biosynthesis likely proceeds through a domain formation stage.