Modular Arrangement of Allelic Variants Explains the Divergence in Moraxella catarrhalis UspA Protein Function

Abstract

Ubiquitous surface protein A molecules (UspAs) of Moraxella catarrhalis are large, nonfimbrial, autotransporter proteins that can be visualized as a "fuzzy" layer on the bacterial surface by transmission electron microscopy. Previous studies attributed a wide array of functions and binding activities to the closely related UspA1, UspA2, and/or UspA2H protein, yet the molecular and phylogenetic relationships among these activities remain largely unexplored. To address this issue, we determined the nucleotide sequence of the uspA1 genes from a variety of independent M. catarrhalis isolates and compared the deduced amino acid sequences to those of the previously characterized UspA1, UspA2, and UspA2H proteins. Rather than being conserved proteins, we observed a striking divergence of individual UspA1, UspA2, and UspA2H proteins resulting from the modular assortment of unrelated "cassettes" of peptide sequence. The exchange of certain variant cassettes correlates with strain-specific differences in UspA protein function and confers differing phenotypes upon these mucosal surface pathogens.

Molecular Aspects ofMoraxella catarrhalisPathogenesis

“…In contrast, the N-terminal part of UspA2 is highly divergent from UspA2 and UspA2H. Furthermore, UspA1 and UspA2 both have variable stalk regions, harboring the UspA1 and UspA2 variable regions (U1VR and U2VR, respectively) (22). Sequence variability of the UspA2H stalk region (tentatively designated U2HVR) has not yet been determined.…”

“…The N-terminal globular head domain (passenger domain) is most readily available for binding because it extends beyond the outer membrane. UspA1 and UspA2 share homology in the stalk region but display major differences in the head-and membrane-anchoring domains (22). In fact, the UspA proteins of different isolates are divergent but share several (apparently) interchangeable modular amino acid sequence cassettes (Fig.…”

“…The UspA1 C-terminal region is highly conserved among isolates and is composed of a NINNY-KASS-FET motif followed by C-terminal region 1. UspA2 variants are also highly conserved at the C terminus, possessing the C-terminal region 2 domain flanked by the NINNY-KASS-FET motif, except for that of M. catarrhalis strain TTA24, which possesses an incomplete carcinoembryonic antigen-related cellular adhesion molecule 1 (CEACAM1)-binding motif (see below) instead of the FET motif (22). Several groups have studied the functional role of UspAs in adhesion to human cell lines.…”

Immune Evasion ofMoraxella catarrhalisInvolves Ubiquitous Surface Protein A-Dependent C3d Binding

“…The hybrid UspA2H consists of UspA1 and UspA2 with its N-terminal (head region) and C-terminal (near-end stalk and membrane-anchored region) having shared sequence similarity with UspA1 and UspA2, respectively (17,19,20). The stalk region is highly conserved between UspA1, UspA2, and UspA2H of different strains (17,19,21). The UspAs bind the extracellular matrix proteins laminin and fibronectin and are essential for attachment of M. catarrhalis to epithelial cells (17,(22)(23)(24), and they play important roles in M. catarrhalis serum resistance by interacting with C3, C4b-binding protein (C4BP), and vitronectin (25)(26)(27)(28).…”

“…UspA1 and UspA2 are multifunctional proteins, have highly conserved epitopes, and thus are of considerable interest as potential vaccine candidates (9,18). The hybrid UspA2H consists of UspA1 and UspA2 with its N-terminal (head region) and C-terminal (near-end stalk and membrane-anchored region) having shared sequence similarity with UspA1 and UspA2, respectively (17,19,20). The stalk region is highly conserved between UspA1, UspA2, and UspA2H of different strains (17,19,21).…”