The Small β-Barrel Domain: A Survey-Based Structural Analysis

Abstract

The small b-barrel (SBB) is an ancient protein structural domain characterized by extremes: it features a broad range of structural varieties, a deeply intricate evolutionary history, and it is associated with a bewildering array of cellular pathways. Here, we present a thorough, survey-based analysis of the structural properties of SBBs. We first consider the defining properties of the SBB, including various systems of nomenclature used to describe it, and we introduce the unifying concept of an ''urfold.'' To begin elucidating how vast functional diversity can be achieved by a relatively simple domain, we explore the anatomy of the SBB and its representative structural variants. Many SBB proteins assemble into cyclic oligomers as the biologically functional units; these oligomers often bind RNA, and typically exhibit great quaternary structural plasticity (homomeric and heteromeric rings, variable subunit stoichiometries, etc.). We conclude with three themes that emerge from the rich structure 4 function versatility of the SBB.Strand b1 is red, b2 is orange, b3 is yellow, and b4 is green; for the SH3 and OB folds, the fifth strand is also shown (gray). Branches along a sample path in this digraph are highlighted in tan (subtree at right), yielding the 1 Zhang and Kim, 2000); these two sheets, near the center of the image, are drawn simply to illustrate tree traversal. The base of the overall tree (at center) is a decision between the two possible configurations (parallel, antiparallel) for the simplest possible sheet-i.e., a tandem pair of strands (⇨∿∿⇨). Traversing the tree from this split ''root'' to the leaves corresponds to building-up the sheet, and the tree's branching structure elucidates the n!• •2 nÀ2 unique topologies that are possible for a sheet of n strands; the successive branches of this unrooted k-ary tree are of degrees 2, 6, 2, 2, 2. The positions of the SH3 and OB folds are indicated by cyan and purple paths (subtree at left). Other features of b-sheets are also elucidated by this hierarchical representation, such as the fact that there are 24 unique arrangements of two sequentially adjacent b-hairpin motifs (red circles, left subtree). If the origin for strand numbering is taken as arbitrary (e.g., labeling a sequence 2/3/4 does not differ from 1/2/3), then the OB topology (pink path, left) can be seen to cluster closely with the SH3; the yellow region delimits a putative SBB ''urfold'' basin in fold-space, subsuming the SH3 and OB folds.

The Urfold: Structural similarity just above the superfold level?

“…Along with 10 additional folds that have similar overall architectures, we recently termed these superfolds the "small β-barrel" (SBB) domain. 29 Cases similar to that described above for the SBB can be found with other folds. Indeed, such a confounding mixture of effects-one largely evolutionary (homology, divergent) and the other more physicochemical (analogy, convergent)-might hold even within the SH3 superfold itself.…”

“…We suspect that highly gregarious folds are archetypal Urfolds. When part of a larger domain, we require an Urfold to be central to the structural core (versus, e.g., a peripheral element or other "decoration," in the sense of examples in the work of Youkharibache et al 29 ). At one extreme, a free-standing helix or β-strand (or even β-hairpin) is too small to be an Urfold, and in the other limit, a two-domain protein is too large.…”

“…23,45 In fact, in the CATH system, the SH3 and OB domains even belong to two distinct architectures (2.40.50 [OB] and 2.30.30 [SH3]). 29 The sequence similarities among members of each fold within the SBB urfold (as well as between the SH3 and OB folds) are often minimal (below the twilight zone), perhaps because of both homologous and analogous relationships between the individual entities. Along with 10 additional folds that have similar overall architectures, we recently termed these superfolds the "small β-barrel" (SBB) domain.…”

“…The type of progression shown in Figure 2c helps elucidate these questions by showing the relationships (equivalencies, alterations) between individual folds within a single putative Urfold. In a decision tree-based approach to systematizing β-structures, 29 these four proteins form a natural progression, with 1ELO more distant from 1M5Q than are 1XXA and 1VHH. Somewhat similar in spirit, toy models could be used together with a machine learning-based fold classifier to examine the relationship between classification results and systematically varied geometric descriptors, such as the crossover angle between helices (e.g., as part of a helix-turn-helix motif or, more distant in sequence, as tertiary contact sites).…”

“…Finally, Figure 2d illustrates the small β-barrel (SBB) domain, which we propose is an Urfold that aggregates the SH3/Sm and OB superfolds. 29 The SBB spurs the question of whether a particular Urfold might be part of a larger structural unit (e.g., a large-sized domain)? For example, the ferredoxin reductase (FR)-like fold, found within a recent structure of a siderophore-interacting protein (SIP; 6GEH), bears "a certain resemblance" 23 to the SBB, as shown in Figure 2d.…”