Principles of Protein Structural Organization - H. Schulz 1982

Mechanisms of polypeptide chain folding and association
Globular proteins

Globular Proteins consist of one or more Structural domains. A globular protein is generally defined as the folding product of a single polypeptide chain. Consequently, globular proteins typically comprise one or more structural domains. In some cases (such as Ser-proteases, IMMUNOGLOBULINS, and rhodanase), the domains are so strikingly similar that Gene Duplication can be reasonably inferred. Each domain can be assigned to one of the five classes listed in Table 5.2. There is no evident preference for structural domains of a single globular protein to belong to the same Class (Table 5.2). To date, no notable correlation has been found between the structural class and the function of either the domain or the globular protein. However, nucleotide-binding domains typically belong to Class No. 4. Furthermore, it has been observed that all glycolytic Enzymes with known structures also belong to this same Class No. 4.

Enzyme active sites generally incorporate portions of all structural domains of a globular protein. The active sites of all known multidomain proteins (Table 5.2) are located between the domains (Fig. 4.1). These domains are defined not only as globular regions separated by the Active Site cleft, but also exhibit another characteristic property of domains: they are linked to one another by a single peptide chain (Table 5.2). Substrates and Cofactors typically bind to different domains. In the case of NAD, the cofactor-binding domain consistently displays the same topology with a well-developed open surface, and NAD binds at equivalent positions (Fig. 5.17, b), a feature resulting from molecular evolution [254, 255]. Moreover, this domain has been found at the N-terminus of three dehydrogenases and one kinase [230–233, 235], as well as in the C-terminal half of a fourth dehydrogenase [234] and in the middle region of phosphorylase [236], indicating the possibility of corresponding gene duplication and translocation within The Genome. All these facts—the participation of parts from different domains in the active site, the presence of cofactor-specific domains, and the potential for domain mobility—suggest that enzymes are assembled using a modular system: cofactor- and substrate-specific domains required for a given function are selected and combined within a single globular protein chain [124, 256].