Proteindomain

A protein domain is defined as a region of the polypeptide chain of a protein that is self-stabilizing and folds independently of the rest of the molecule. This domain area usually contains between 50 and 350 amino acid residues. Small proteins often contain only one domain. Larger proteins may contain several domains. Domains are connected to each other by low-structure chain regions. The shortest domains, such as the zinc finger domain, are stabilized by metal ions or disulfide bridges, for example. Each domain thus forms a compact, stable, three-dimensionally folded structure. Many domain families are found in all three life forms, Archaea, Bacteria and Eukarya (Wheelan SJ et al. 2000).

Many proteins are built up modularly from an assembly of different protein domains, which only in this combination produce the specific function of the protein. As a modular building block, a protein domain can lead to different functions in a wide variety of proteins. This evolutionary principle allows a high speed in the creation of new proteins, as they can be assembled from already existing peptide building blocks (Wheelan SJ et al. 2000).

Domains often form functional units, such as the calcium-binding EF-hand domain of calmodulin. In a multidomain protein, each domain may perform its own function independently, or it may perform a function in a concerted approach with its neighbors. Domains can either serve as modules for building large assemblies such as viral particles or muscle fibers (structural proteins), or they can also provide specific catalytic or binding sites (functional proteins). This is the case in enzymes or regulatory proteins.

Primary structure of proteins: The primary structure (string of amino acids) of a protein ultimately defines its folded three-dimensional (3D) conformation (Anfinsen CB et al. (1961). The most important factor determining the folding of a protein into its 3D structure is the distribution of polar and nonpolar side chains (Jones S et al. (1998).In general, proteins have a core of hydrophobic residues surrounded by a shell of hydrophilic residues. Since the peptide bonds themselves are polar, they are neutralized by hydrogen bonds between them when they are in the hydrophobic environment. This creates regions of the polypeptide that form regular 3D structural patterns called secondary structure.

Two main types of secondary structures are observed: α-helices and β-sheets. Some simple combinations of secondary structure elements occur frequently in protein structure and are called super secondary structure or motifs. A common supersecondary structure is the β-α-β motif, which is often used to connect two parallel β-strands. The central α-helix connects the C-termini of the first strand to the N-termini of the second strand, packing its side chains against the β-sheet and thus shielding the hydrophobic residues of the β-strands from the surface. The covalent association of two domains represents a functional and structural advantage, as there is an increase in stability compared to the same structures that are not covalently associated (Cordes MH et al. 1996)

Tertiary structure of proteins: Domains are the basic units of tertiary structure, each domain containing an individual hydrophobic core built up of secondary structural units connected by loop regions (Anfinsen CB et al 1961). The packing of the polypeptide is usually much denser on the interior than on the exterior of the domain, resulting in a solid-like core and a liquid-like surface. Molecular evolution gives rise to families of related proteins with similar sequence and structure. Here, it is likely that some folds are preferred because they represent stable arrangements of secondary structures. Approximately 110,000 experimentally determined 3D structures of proteins are stored in the various protein databases.

Protein domain databases

• Pfam: Pfam contains the families of protein domains. With the help of known domains, the user can infer a similar function or an evolutionary relationship via a sequence comparison in an unknown protein.
• ProDom: ProDom contains protein domains derived from sequences from SWISS-PROT and TrEMBL. Furthermore, the domain structure of a protein can be displayed graphically.
• SMART: SMART is the abbreviation for Simple Modular Architecture Research Tool and is a database of protein domain families. The user can obtain information about the function, important amino acids, phylogenetic development and tertiary structure of these domains.
• CDD: CDD stands for Conserved Domain Database and is a database where one can query domains and the corresponding sequence alignment. The entries here are derived from Pfam, SMART and COG.
• HITS: The HITS database can be used to query protein domains.
• InterPro: The InterPro provides a description of protein family function, literature references and cross-references. Information is compiled by integrating various databases such as PROSITE, PRINTS, Pfam and ProDom.
• DALI Domain Dictionary: The DALI dictionary of domains makes an automatic classification of protein domains based on sequence matches. With this dictionary, the user can compare 3-D protein structures and identify structural domains that are similar in two different proteins even though the sequences are different.

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