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Abstract
Integrins are heterodimeric cell-surface receptors with key functions in cell-cell and cell-matrix adhesion. Integrin α and β subunits are present throughout the metazoans, but it is unclear whether the subunits predate the origin of multicellular organisms. Several component domains have been detected in bacteria, one of which, a specific 7-bladed β-propeller domain, is a unique feature of the integrin α subunits. Here, we describe a structure-derived motif, which incorporates key features of each blade from the X-ray structures of human αIIbβ3 and αVβ3, includes elements of the FG-GAP/Cage and Ca2+-binding motifs, and is specific only for the metazoan integrin domains. Separately, we searched for the metazoan integrin type β-propeller domains among all available sequences from bacteria and unicellular eukaryotic organisms, which must incorporate seven repeats, corresponding to the seven blades of the β-propeller domain, and so that the newly found structure-derived motif would exist in every repeat. As the result, among 47 available genomes of unicellular eukaryotes we could not find a single instance of seven repeats with the motif. Several sequences contained three repeats, a predicted transmembrane segment, and a short cytoplasmic motif associated with some integrins, but otherwise differ from the metazoan integrin α subunits. Among the available bacterial sequences, we found five examples containing seven sequential metazoan integrin-specific motifs within the seven repeats. The motifs differ in having one Ca2+-binding site per repeat, whereas metazoan integrins have three or four sites. The bacterial sequences are more conserved in terms of motif conservation and loop length, suggesting that the structure is more regular and compact than those example structures from human integrins. Although the bacterial examples are not full-length integrins, the full-length metazoan-type 7-bladed β-propeller domains are present, and sometimes two tandem copies are found.
Highlights
Integrins are large, heterodimeric cell-surface receptors that detect and transmit changes in mechanical forces resulting from interactions between a cell and the extracellular matrix [1]
Half of the integrin a subunits in human, namely a1, a2, a10, a11, aL, aM, aX, aD, and aE, contain an additional domain – a von Willebrand factor type-A domain, inserted between the second and the third blades of the N-terminal 7bladed b-propeller domain, referred to as either the aA domain [5] or the aI domain [6]; the b-propeller domain is found in all integrin a subunits
All integrins with an inserted aI domain bind their natural ligands via the metal ion dependent adhesion site (MIDAS) of the aI domain and appear to have arisen within integrin a subunits around the divergence of the first chordates since they are found in some integrin a subunits from tunicates but not from the earliest-diverging deuterostomes, e.g. the echinoderms [7,8,9]
Summary
Heterodimeric cell-surface receptors that detect and transmit changes in mechanical forces resulting from interactions between a cell and the extracellular matrix [1]. On closer inspection of the alignments it is was clear that the bacterial sequences matched the repeating units corresponding to blades of the b-propeller domain, but that the reported sequences did not include the trans-membrane domain, and the Thigh, Calf-1, or Calf-2 domains were not recognizable in the sequences It remained unclear whether the repeating units that were observed in bacteria would indicate the presence of an integrin-like 7-bladed b-propeller or a bpropeller formed from a different number of blades, or if they represented an entirely different fold. We present strong evidence that bacterial sequences encode structures that are equivalent to the 7-bladed b-propeller found in human integrins
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