Motifs Supersecondary Structures

Sometimes motifs are also used interchangeably with patterns to describe recurring, conserved sequences of functional significance derived from sequence/structure alignment studies. In this usage, motifs (patterns) are commonly associated with specific functions of homologous proteins (Table 5.6). 

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The architecture of protein molecules is complex and can be described according to structural organization as primary structure (amino acid sequence), secondary structure (regular structures such as helical, pleated sheet, and coil stractures), tertiary structure (fold in three-dimensional space), quaternary structure (subunit structure) and quintemary structure (biomacromolecular complexes). Usually the overall three-dimensional (3D) architecture of a protein molecule is termed as its conformation, which refers to its secondary and tertiary structures. Between these two stractures, motifs (supersecondary structures) refer to the packing of adjacent secondary stractures into distinct structural elements and domains refer to identifiable 3D structural units that may correspond to functional units. The structures of most proteins with more than 200 amino acid residues appear to consist of two or more domains. 

Simple combinations of a few secondary strucfure elements with a specific geometric arrangement have been found to occur frequently in protein structures. These units have been called either supersecondary structures or motifs. We will use the term "motif" throughout this book. Some of these motifs can be associated with a particular function such as DNA binding others have no specific biological function alone but are part of larger strucfural and functional assemblies. 

The helix-turn-helix scaffold is designed to dimerize into a four-helix bundle. Modification of the peptide with the nicotinoyl functionality did not significantly perturb the peptide structure. CD spectroscopy showed no loss in helici-ty from the parent peptide and NMR spectroscopy confirmed successful incorporation of the nicotinoyl group as well as maintenance of crucial NOE connectivities. In particular, the presence of long-range NOE signals between the side chains of phenylalanine 38 and leucine 12 or isoleucine 9, which lie near the C- and AT-termini, respectively, demonstrate that the supersecondary structure of the motif has been conserved. 

The size and complexity of the motif is clearly important, single hehces are of limited use because of the long intra-residue distances on the helical surface (Fig. 2) and functions that require more than two-residue sites will most hkely have to depend on the functionahzation of supersecondary structures. The clever designs of catalysts for decarboxylation and hgation reactions are, on the other hand, good examples of how small motifs can be exploited for complex functions [11,12]. 

Supersecondary structures, also called motifs or simply folds, are particularly stable arrangements of several elements of secondary structure and the connections between them. There is no universal agreement... 

Globular proteins are constructed by combining secondary structural elements (a-helices, 3-sheets, nonrepetitive sequences). These form primarily the core region—that is, the interior of the molecule. They are connected by loop regions (for example, 3-bends) at the surface of the protein. Supersecondary structures are usually pro duced by packing side chains from adjacent secondary structural elements close to each other. Thus, for example, a-helices and 3-sheets that are adjacent in the amino acid sequence are also usu ally (but not always) adjacent in the final, folded protein. Some of the more common motifs are illustrated in Figure 2.8. 

Supersecondary structures (motifs) are produced by packing side chains from adjacent secondary structural elements close to each other. 

Frequently recurring substructures or folds are collectively termed supersecondary structures or motifs. These are combinations of a and/or j8 structure. A simple example is a /8 hairpin, consisting of two antiparallel strands joined by a loop of three to five residues (Figure 1.12). This frequently occurs in antiparallel P sheet. Such sheet frequently contains four p strands connected as in Figure 1.13 in a motif called a Greek key (or meander, which is the Greek word for the pattern) because it is reminiscent of the Greek decorative motif, or six strands described as a jellyroll. 

Sun, Z. Jiang, B. (1996). Patterns and conformations of commonly occurring supersecondary structures (basic motifs) in protein data bank. J Protein Chem 15,675-90. 

FIGURE 3.12 Supersecondary structures found in proteins (a) p—a—p motif (b) antiparallel p-sheets connected by hairpin loops and (c) Qc—Qc motif. 

Certain combinations of secondary structure are present in many proteins and frequently exhibit similar functions. These combinations are called motifs or supersecondary structure. For example, an a helix separated from another a helix by a turn, called a helix-turn-helix unit, is found in many proteins that bind DNA (Figure 2.51). 

There is a natural hierarchy in proteins (see Figure 15.1) which allows the complex three-dimensional structure to be simplified and categorized as combinations of smaller motifs. At the atom level there are patterns of side-chain interactions at the backbone level we see formation of secondary structure (a helix, P sheet and yS turn) and loop families these combine to give supersecondary structures (e.g. P hairpins) and motifs (e.g. Greek key) and ultimately the whole tertiary and quaternary structure. In this chapter we present an overview of current patterns which are observed... 

FIGURE 4.9 Motifs and modules. Motifs are repeated supersecondary structures, sometimes called modules. All of these have a particular secondary structure that is repeated in the protein. (Reprinted from Protein Modules, "Trends in Biochemical Sciences, Vol. 16, pp. 13—17, Copyright 1991, xvith permission from Elsevier.)... 

The most common secondary structures are the a-helix and /3-sheet. Native proteins may have combinations of various secondary structures Regions of secondary structures can be combined to form supersecondary structures, motifs, and domains. 

Many proteins share structural similarities due to the evolutionary process involving substitutions, insertions and deletions in amino add sequences. Consequently protein structures can be characterized according to their connnon substructures (supersecondary structures, e.g. motifs, domains). For proteins with conserved functions, the structural environments of critical active site residues are also conserved. In an attempt to better understand seqnence-structuie relationships and the underlying evolutionary processes that give rise to different fold famihes, a variety of structure classification schemes have been established. Analyses of the 3D structures archived in PDB generate various databases for the specification/search of characteristic substructures and protein structure classifications (Table 16.6). 

A description of the protein-structure hierarchy is incomplete without a discussion of structural motifs, which are critical to an understanding of protein structure [17]. Identification of recurring motifs in protein structures has refined our knowledge of the protein-structure hierarchy these motifs occur at all levels from primary to tertiary. The Phe-Asp-Thr-Gly-Ser sequence found in the active site of all aspartic acid proteinases, and the Gly-Gly-X-Leu sequence (where X represents any amino acid residue) that predicts a 3-strand for the last two residues [17], are examples of sequence motifs a-helices, P-strands, and turns are examples of secondary-structural motifs PaP and PxP units, P-hairpins, and Greek keys are examples of supersecondary-structural motifs and four-a-helix bundles and TIM barrels are examples of tertiary-structural motifs. The tertiary fold of a protein is characterized by its tertiary-structural motif. 

Due to the small number of secondary-structural types found in proteins, only a limited number of simple supersecondary-structural motifs such as aa, PP, PaP,..., are possible. Moreover, as discussed by Chothia and co-workers in a number of papers [23,24], the packing geometries available to each supersecondary-structural motif are also quite limited specifically, the relative orientations of two a-helices, of an a-helix and a P-sheet, and of two P-sheets exhibit limited distributions. These disuibutions have been interpreted both in geometric terms, based on the surface topography of the interacting secondary-structural elements [20,23-26], and in energetic terms, based on the molecular mechanics calculations of Chou et al [27]. 

According to X-ray and NMR analysis, a number of proteins which regulate gene expression possess a supersecondary structure, known as a helix-turn-helix (HTH) motif. The HTH motif consists of two symmetrically arranged a-helical structures, each containing about 20 residues with similar primary structures. The helices cross at about 120°, and are spaced in such a way that they can bind two sequential turns of the major groove of the DNA helix, Samples of regulatory proteins that possess a HTH motif are ... 

F. M. Richards and C. E. Kundrot, Proteins Struct., Function Genet., 3, 71 (1988). Identification of Structural Motifs from Protein Coordinate Data Secondary Structure and First-Level Supersecondary Structure. 

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